Polymorphisms associated with hypertension

ABSTRACT

The invention discloses a collection of polymorphic sites in genes know or suspected to have a role in hypertension. The invention provides nucleic acids including such polymorphic sites. The nucleic acids can be used as probes or primers or for expressing variant proteins. The invention also provide methods of analyzing the polymorphic forms occupying the polymorphic sites.

CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application derives priority from U.S. Ser. No. 60/084,641filed May 7, 1998, which is incorporated by reference in its entiretyfor all purposes.

[0002] The work described in this application was funded, in part, by agrant from the National Heart, Lung & Blood Institute (U10 HL54466),which may have certain rights in this invention.

BACKGROUND OF THE INVENTION

[0003] Hypertension, or high blood pressure, is a common diseaseaffecting 50 million Americans and contributing to over 200,000 deathsannually from stroke, myocardial infarction, and end-stage renaldisease. The disease is multifactorial and numerous genetic andnongenetic components, such as salt intake, age, diet, and body mass,are suspected to contribute. A specific cause of hypertension cantypically be identified in only a small percentage of patients. Otherpatients with abnormally high blood pressure of unknown cause are saidto have essential hypertension.

[0004] The existence of a genetic component to hypertension is knownfrom twin studies, which have revealed a greater concordance of bloodpressure in monozygotic twins that in dizygotic twins. Similarly,biological siblings have show greater concordance of blood pressure thanadoptive siblings raised in the same household. Such studies havesuggested that up to about 40% of the variations in blood pressure inthe population are genetically determined.

[0005] There is a substantial pool of candidate genes that maycontribute to the genetic component of hypertension. Because bloodpressure is determined by the product of cardiac output and vascularresistance, candidate genes may act through either pathway. Physiologicpathways which are know to influence these parameters include therenin-angiotensin-aldosterone system, which contributes to determinationof both cardiac output and vascular resistance. In this pathway,angiotensinogen, a hormone produced in the liver, is cleaved by anenzyme called renin to angiotensin I, which then undergoes furthercleavage by angiotensin I-converting enzyme (ACE) to produce the activehormone angiotensin II (AII). All acts through specific AT1 receptorspresent on vascular and adrenal cells. Receptors present on vascularcells cause vasoconstriction of blood vessels. Receptors present onadrenal cells cause release of the hormone aldosterone by the adrenalgland. This hormone acts on the mineralocorticoid receptor to causeincrease sodium reabsorption largely through a renal epithelial sodiumlocation. Other candidate genes are those of peripheral and centraladrenergic pathways, which have dominant effects on cardiac iontropy,heart rate and vascular resistance; a variety of renal ion channels andtransporters, which determine net sodium absorption and henceintravascular volume; calcium channels and exchangers and nitric oxidepathways, whose activity influences vascular tone. Another candidategene encodes atrial natriuretic factor precursor, which is cleaved toatrial natriuretic peptides, found in the heart atrium, an endocrineorgan controlling blood pressure and organ volume.

[0006] For some of the above candidate genes, variant forms have beenidentified that occur with increased frequency in individuals withhypertension. For example, a number of the polymorphisms have beenreported in the angiotensinogen gene (AGT). In one of these, an M/Tsubstitution at position 235, the T allele occurs more frequently inindividuals with hypertension suggesting that this polymorphic form is acause of hypertension or in equilibrium dislinkage with anotherpolymorphism that is a cause. Jeunmaitre et al., Am. J. Hum. Genet. 60,1448-1460 (1997). Two other genes within therenin-angiotensin-aldosterone system also have variant forms correlatedwith specific forms of hypertension, that is, aldosterone synthase geneand the gene encoding the β-subunit of the epithelial sodium channelinduced by the mineralocorticoid receptor. Lifton et al., Proc. Natl.Acad. Sci. USA 92, 8548-8551 (1995).

[0007] Despite these developments, only a minute proportion of the totalrepository of polymorphisms in candidate genes for hypertension has beenidentified, and the primary genetic determinants of hypertension remainunknown in most affected subjects, as does the nature of the interactionbetween different genetic determinants. The paucity of polymorphismshitherto identified is due to the large amount of work required fortheir detection by conventional methods. For example, a conventionalapproach to identifying polymorphisms might be to sequence the samestretch of oligonucleotides in a population of individuals by dideoxysequencing. In this type of approach, the amount of work increases inproportion to both the length of sequence and the number of individualsin a population and becomes impractical for large stretches of DNA orlarge numbers of persons.

SUMMARY OF THE INVENTION

[0008] The invention provides nucleic acids of between 10 and 100 basescomprising at least 10 contiguous nucleotides including a polymorphicsite from a sequence shown in Table 1, column 8 or the complementthereof. The nucleic acids can be DNA or RNA. Some nucleic acids arebetween 10 and 50 bases and some are between 20 and 50 bases. The baseoccupying the polymorphic site in such nucleic acids can be either areference base shown in Table 1, column 3 or an alternative base shownin Table 1, column 5. In the some nucleic acids, the polymorphic site isoccupied by a base that correlates with hypertension or susceptibilitythereto. Some nucleic acids contain a polymorphic site having twopolymorphic forms giving rise two different amino acids specified by thetwo codons in which the polymorphic site occurs in the two polymorphicforms.

[0009] The invention further provides allele-specific oligonucleotidesthat hybridize to a nucleic acid segment shown in Table 1, column 8 orits complement, including the polymorphic site. Such oligonucleotidesare useful as probes or primers.

[0010] The invention further provides methods of analyzing a nucleicacid sequence. Such methods entail obtaining the nucleic acid from anindividual; and determining a base occupying any one of the polymorphicsites shown in Table 1 or other polymorphic sites in equilibriumdislinkage therewith. Some methods determine a set of bases occupying aset of the polymorphic sites shown in Table 1. In some methods, thenucleic acid is obtained from a plurality of individuals, and a baseoccupying one of the polymorphic positions is determined in each of theindividuals. Each individual is then tested for the presence of adisease phenotype, and correlating the presence of the disease phenotypewith the base, particularly hypertension.

[0011] In another aspect, the invention provides nucleic acidscomprising an isolated nucleic acid sequence of Table 1, column 8 or thecomplement thereof, wherein the polymorphic site within the sequence orits complement is occupied by a base other than the reference base showin Table 1, column 3. Such nucleic acids are useful, for example, inexpression of variant proteins or production of transgenic animals.

[0012] The invention further provides methods of diagnosing a phenotype.Such methods entail determining which polymorphic form(s) are present ina sample from a subject at one or more polymorphic sites shown in Table1, and diagnosing the presence of a phenotype correlated with theform(s) in the subject.

[0013] The invention also provides methods of screening polymorphicsites linked to polymorphic sites shown in Table 1 for suitability fordiagnosing a phenotype. Such methods entail identifying a polymorphicsite linked to a polymorphic site shown in Table 1, wherein apolymorphic form of the polymorphic site shown in Table 1 has beencorrelated with a phenotype. One then determines haplotypes in apopulation of individuals to indicate whether the linked polymorphicsite has a polymorphic form in equlibrium dislinkage with thepolymorphic form correlated with the phenotype.

BRIEF DESCRIPTION OF THE DRAWINGS

[0014]FIGS. 1A and 1B depict computer systems suitable for storing andtransmitting information relating to the polymorphisms of the invention.

DEFINITIONS

[0015] A nucleic acid can be DNA or RNA, and single- or double-stranded.Oligonucleotides can be naturally occurring or synthetic, but aretypically prepared by synthetic means. Preferred nucliec acids of theinvention include segments of DNA, or their complements including anyone of the polymorphic sites shown in Table 1. The segments are usuallybetween 5 and 100 contiguous bases, and often range from 5, 10, 12, 15,20, or 25 nucleotides to 10, 15, 30, 25, 20, 50 or 100 nucleotides.Nucleic acids between 5-10, 5-20, 10-20, 12-30, 15-30, 10-50, 20-50 or20-100 bases are common. The polymorphic site can occur within anyposition of the segment. The segments can be from any of the allelicforms of DNA shown in Table 1. For brevity in Table 1, the symbol T isused to represent both thymidine in DNA and uracil in RNA. Thus, in RNAoligonucleotides, the symbol T should be construed to indicate a uracilresidue.

[0016] Hybridization probes are capable of binding in a base-specificmanner to a complementary strand of nucleic acid. Such probes includenucleic acids, peptide nucleic acids, as described in Nielsen et al.,Science 254, 1497-1500 (1991).

[0017] The term primer refers to a single-stranded oligonucleotidecapable of acting as a point of initiation of template-directed DNAsynthesis under appropriate conditions (i.e., in the presence of fourdifferent nucleoside triphosphates and an agent for polymerization, suchas, DNA or RNA polymerase or reverse transcriptase) in an appropriatebuffer and at a suitable temperature. The appropriate length of a primerdepends on the intended use of the primer but typically ranges from 15to 30 nucleotides. Short primer molecules generally require coolertemperatures to form sufficiently stable hybrid complexes with thetemplate. A primer need not reflect the exact sequence of the templatebut must be sufficiently complementary to hybridize with a template. Theterm primer site refers to the area of the target DNA to which a primerhybridizes. The term primer pair means a set of primers including a 5′upstream primer that hybridizes with the 5′ end of the DNA sequence tobe amplified and a 3′, downstream primer that hybridizes with thecomplement of the 3′ end of the sequence to be amplified.

[0018] Linkage describes the tendency of genes, alleles, loci or geneticmarkers to be inherited together as a result of their location on thesame chromosome, and can be measured by percent recombination betweenthe two genes, alleles, loci or genetic markers. Loci occurring within50 centimorgan of each other are linked. Some linked markers occurwithin the same gene or gene cluster.

[0019] Polymorphism refers to the occurrence of two or more geneticallydetermined alternative sequences or alleles in a population. Apolymorphic marker or site is the locus at which divergence occurs.Preferred markers have at least two alleles, each occurring at frequencyof greater than 1%, and more preferably greater than 10% or 20% of aselected population. A polymorphic locus may be as small as one basepair. Polymorphic markers include restriction fragment lengthpolymorphisms, variable number of tandem repeats (VNTR's), hypervariableregions, minisatellites, dinucleotide repeats, trinucleotide repeats,tetranucleotide repeats, simple sequence repeats, and insertion elementssuch as Alu. The first identified allelic form is arbitrarily designatedas a the reference form and other allelic forms are designated asalternative or variant alleles. The allelic form occurring mostfrequently in a selected population is sometimes referred to as thewildtype form. Diploid organisms may be homozygous or heterozygous forallelic forms. A dialletic polymorphism has two forms. A triallelicpolymorphism has three forms.

[0020] A single nucleotide polymorphism occurs at a polymorphic siteoccupied by a single nucleotide, which is the site of variation betweenallelic sequences. The site is usually preceded by and followed byhighly conserved sequences of the allele (e.g., sequences that vary inless than {fraction (1/100)} or {fraction (1/1000)} members of thepopulations).

[0021] A single nucleotide polymorphism usually arises due tosubstitution of one nucleotide for another at the polymorphic site. Atransition is the replacement of one purine by another purine or onepyrimidine by another pyrimidine. A transversion is the replacement of apurine by a pyrimidine or vice versa. Single nucleotide polymorphismscan also arise from a deletion of a nucleotide or an insertion of anucleotide relative to a reference allele.

[0022] A set of polymorphisms means at least 2, and sometimes 5, 10, 20,50 or more of the polymorphisms shown in Table 1.

[0023] Hybridizations are usually performed under stringent conditions,for example, at a salt concentration of no more than 1 M and atemperature of at least 25□C. For example, conditions of 5×SSPE (750 mMNaCl, 50 mM Na Phosphate, 5 mM EDTA, pH 7.4) and a temperature of25-30□C. are suitable for allele-specific probe hybridizations.

[0024] An isolated nucleic acid means an object species invention thatis the predominant species present (i.e., on a molar basis it is moreabundant than any other individual species in the composition).Preferably, an isolated nucleic acid comprises at least about 50, 80 or90 percent (on a molar basis) of all macromolecular species present.Most preferably, the object species is purified to essential homogeneity(contaminant species cannot be detected in the composition byconventional detection methods).

[0025] Linkage disequilibrium or allelic association means thepreferential association of a particular allele or genetic marker with aspecific allele, or genetic marker at a nearby chromosomal location morefrequently than expected by chance for any particular allele frequencyin the population. For example, if locus X has alleles a and b, whichoccur equally frequently, and linked locus Y has alleles c and d, whichoccur equally frequently, one would expect the haplotype ac to occurwith a frequency of 0.25 in a population of individuals. If ac occursmore frequently, then alleles a and c are in linkage disequilibrium.Linkage disequilibrium may result from natural selection of certaincombination of alleles or because an allele has been introduced into apopulation too recently to have reached equilibrium with linked alleles.

[0026] A marker in linkage disequilibrium can be particularly useful indetecting susceptibility to disease (or other phenotype) notwithstandingthat the marker does not cause the disease. For example, a marker (X)that is not itself a causative element of a disease, but which is inlinkage disequilibrium with a gene (including regulatory sequences) (Y)that is a causative element of a phenotype, can be used detected toindicate susceptibility to the disease in circumstances in which thegene Y may not have been identified or may not be readily detectable.Younger alleles (i.e., those arising from mutation relatively late inevolution) are expected to have a larger genomic sequencement in linkagedisequilibrium. The age of an allele can be determined from whether theallele is shared between ethnic human groups and/or between humans andrelated species.

DETAILED DESCRIPTION

[0027] The invention provides a substantial collection of novelpolymorphisms in several genes encoding products known or suspected tohave roles in biochemical pathways relating to blood pressure. Detectionof polymorphisms in such genes is useful in designing and performingdiagnostic assays for hypertension. Analysis of polymorphisms is alsouseful in designing prophylactic and therapeutic regimes customized tounderlying abnormalities. As with other human polymorphisms, thepolymorphisms of the invention also have more general applications, suchas forensics, paternity testing, linkage analysis and positionalcloning.

[0028] I. Novel Polymorphisms of the Invention.

[0029] The invention provides polymorphic sites in 75 candidate genes,known or suspected to have roles in hypertension. A gene was designateda candidate based on known or suggested involvement in blood pressurehomeostasis and/or hypertension in one of the following biochemicalpathways: renin-angiotensin, neural, or hormonal pathways regulatingblood pressure; regulation of vascular constriction, growth, and repair;ion and other small molecule transportation pathways in the kidney; and,regulation of glucose metabolism. Experimental evidence supportingselection of candidate genes included blood pressure physiology, animalmodels with altered blood pressure (including transgenic and knockoutmouse or rat animal models), and human genetic linkage and associationstudies.

[0030] To maximize the chances of identifying informative singlenucleotide polymorphisms (SNPs), DNA samples from 40 Africans and 35U.S. individuals of Northern European descent were screened to includeboth a range of human genetic diversity and hypertension phenotypediversity. Human genetic diversity is greater within African, ascompared to European, Asian or American, populations (The History andGeography of Human Genes (Cavalli-Sforza et al., Eds., PrincetonUniversity Press, Princeton, N.J., 1994)). There are also significantdifferences in the prevalence and phenotype of hypertension betweenAfricans (or US Blacks) and Northern Europeans (or US Whites).Hypertension has a greater prevalence, an earlier onset and a higherfrequency of salt-sensitive cases in populations of African descent. Theindividuals sampled were selected from the top and bottom 2.5thpercentile of a normalized blood pressure distribution. Regressionanalysis was performed within each community sample, of systolic,diastolic and mean arterial blood pressure against age and sex, andcalculated the ranked frequency distribution of residuals. Equal numbersof individuals were selected from both ends of this latter distributionto maximize potential genetic differences it the genes screened forSNPs.

[0031] 874 SNPs in 75 individuals were identified at a frequency of oneSNP per 217 bases. 387 SNPs were in coding sequences, 150 in introns,and 337 in 5′ and 3′ UTRs. Of coding sequence chances, 178 and 209 SNPsled to synonymous and nonsynonymouse substitutions in the translatedprotein. On average, 12 SNPs were identified per gene, with the numberranging from zero (HSD11) to 54 (PGIS), with ten genes harboring 20 ormore SNPs.

[0032] A large collection of polymorphisms of the invention are listedin Table 1. The first column of the Table 1 lists the gene and exon inwhich a given polymorphism occurs. For example, ACEEX13 means that apolymorphism occurs in exon 13 of angiotensin I-converting enzyme.AGTEX2 means that a polymorphism occurs in exon 2 of the angiotensinogengene. The full names of the 75 genes shown in Table 1 are shown in Table3. Sequences of each of the genes are available athttp//www.ncbi.nlm.nih.gov/Entrez/nucleotide.html. The second column ofTable 1 shows the position of a polymorphism. Numbering of nucleotidesfollows that of previously published reference sequences withnucleotides in sequence tags shown in column 8 being assigned the samenumber as the corresponding nucleotide in a reference sequence when thetwo are maximally aligned. In general, nucleotides in exons are numberedconsecutively from the first base of the exon. Column 3 shows the baseoccupying the polymorphic position in a previously published sequence(arbitrarily designated a reference sequence). Column 4 of Table 1 showsthe population frequency of the reference allele. For example atposition 138 of exon 13 of ACE, a C nucleotide occurs in 63% of thepopulation. Column 5 of the table shows a nucleotide occupying apolymorphic position that differs from previously published sequences.An allele containing such a nucleotide is designated an alternativeallele. Column 6 of the Table shows the population frequency of thealternative allele. Column 7 of the Table shows the population frequencyof heterozygosity at a polymorphic position. For example, for thepolymorphic position at position 138 of exon 13 of the ACE gene, 37% ofthe human population are heterozygous. A high frequency ofheterozygosity is advantageous in many applications of polymorphisms.The eighth column of the table shows a polymorphic position and about 15nucleotides of flanking sequence on either side. The bases occupying thepolymorphic position are indicated using IUPAC ambiguity nomenclature.For polymorphisms occurring in coding regions, columns 9 and 10 of theTable indicate the codons of the reference and alternate allelesincluding the polymorphic site. These columns are left blank forpolymorphisms occurring in noncoding regions. Column 11 indicateswhether the change between reference and alternate alleles is synonymous(i.e., no amino acid substitution due to polymorphic variation),nonsynonymous (i.e, polymorphic variation causes amino acidsubstitution). If the polymoprhic site does not occur in a codingregion, column 11 characterizes the polymorphic site as “other.” Forpolymorphic sites occurring in noncoding regions column 12 indicates thetype of region in which the site occurs (e.g., 5′ UTR, intron). Forpolymorphic sites occurring in coding regions, column 12 indicates theamino acid encoded by the codon of the reference allele in which thepolymorphic site occurs. Column 13 indicates the amino acid encoded bythe codon of the alternative allele in which the polymorphic siteoccurs.

[0033] The polymorphisms shown in Tables 1 were identified byresequencing of target sequences from unrelated individuals of diverseethnic and geographic backgrounds by hybridization to probes immobilizedto microfabricated arrays. About 190 kb of genomic sequence from 75candidate genes in 75 humans (150 alleles) or about 28 MB total wasanalyze. The sequence included 87 kb coding DNA, 25 kb intron and 77 kbof 5′ and 3′ UTR sequences. Multiple target sequences from an individualwere amplified from human genomic DNA using primers complementary topublished sequences. The amplified target sequences were fluorescentlylabelled during or after PCR.

[0034] Polymorphisms were identified by hybridization of amplified DNAto arrays of oligonucleotide probes. Each genomic region was amplifiedby the polymerase chain reaction (PCR) in multiple segments , rangingfrom 80 bp to 14 kb, by both conventional and long PCR protocols. 205distinct PCR products, averaging 3 kb, representing all 75 genes werepooled for each individual for each chip design

[0035] The strategy and principles for design and use of arrays ofoligonucleotide probes are generally described in WO 95/11995. Thestrategy provides arrays of probes for analysis of target sequencesshowing a high degree of sequence identity to the published sequencesdescribed above. A typical probe array used in this analysis has twogroups of four sets of probes that respectively tile both strands of areference sequence. A first probe set comprises a plurality of probesexhibiting perfect complementarily with one of the reference sequences.Each probe in the first probe set has an interrogation position thatcorresponds to a nucleotide in the reference sequence. That is, theinterrogation position is aligned with the corresponding nucleotide inthe reference sequence, when the probe and reference sequence arealigned to maximize complementarily between the two. For each probe inthe first set, there are three corresponding probes from threeadditional probe sets. Thus, there are four probes corresponding to eachnucleotide in the reference sequence. The probes from the threeadditional probe sets are identical to the corresponding probe from thefirst probe set except at the interrogation position, which occurs inthe same position in each of the four corresponding probes from the fourprobe sets, and is occupied by a different nucleotide in the four probesets. Arrays tiled for multiple different references sequences wereincluded on the same substrate.

[0036] The labelled target sequences were hybridized with a substratebearing immobilized arrays of probes. The amount of label bound toprobes was measured. Analysis of the pattern of label revealed thenature and position of differences between the target and referencesequence. For example, comparison of the intensities of fourcorresponding probes reveals the identity of a corresponding nucleotidein the target sequences aligned with the interrogation position of theprobes. The corresponding nucleotide is the complement of the nucleotideoccupying the interrogation position of the probe showing the highestintensity (see WO 95/11995). The existence of a polymorphism is alsomanifested by differences in normalized hybridization intensities ofprobes flanking the polymorphism when the probes hybridized tocorresponding targets from different individuals. For example, relativeloss of hybridization intensity in a “footprint” of probes flanking apolymorphism signals a difference between the target and reference(i.e., a polymorphism) (see EP 717,113, incorporated by reference in itsentirety for all purposes). Additionally, hybridization intensities forcorresponding targets from different individuals can be classified intogroups or clusters suggested by the data, not defined a priori, suchthat isolates in a give cluster tend to be similar and isolates indifferent clusters tend to be dissimilar. See WO 97/29212, filed Feb. 7,1997 (incorporated by reference in its entirety for all purposes).Hybridizations to samples from different individuals were performedseparately.

[0037] II. Analysis of Polymorphisms

[0038] A. Preparation of Samples

[0039] Polymorphisms are detected in a target nucleic acid from anindividual being analyzed. For assay of genomic DNA, virtually anybiological sample (other than pure red blood cells) is suitable. Forexample, convenient tissue samples include whole blood, semen, saliva,tears, urine, fecal material, sweat, buccal, skin and hair. For assay ofcDNA or mRNA, the tissue sample must be obtained from an organ in whichthe target nucleic acid is expressed.

[0040] Many of the methods described below require amplification of DNAfrom target samples. This can be accomplished by e.g., PCR. Seegenerally PCR Technology: Principles and Applications for DNAAmplification (ed. H. A. Erlich, Freeman Press, NY, N.Y., 1992); PCRProtocols: A Guide to Methods and Applications (eds. Innis, et al.,Academic Press, San Diego, Calif., 1990); Mattila et al., Nucleic AcidsRes. 19, 4967 (1991); Eckert et al., PCR Methods and Applications 1, 17(1991); PCR (eds. McPherson et al., IRL Press, Oxford); and U.S. Pat.No. 4,683,202 (each of which is incorporated by reference for allpurposes).

[0041] Other suitable amplification methods include the ligase chainreaction (LCR) (see Wu and Wallace, Genomics 4, 560 (1989), Landegren etal., Science 241, 1077 (1988), transcription amplification (Kwoh et al.,Proc. Natl. Acad. Sci. USA 86, 1173 (1989)), and self-sustained sequencereplication (Guatelli et al., Proc. Nat. Acad. Sci. USA, 87, 1874(1990)) and nucleic acid based sequence amplification (NASBA). Thelatter two amplification methods involve isothermal reactions based onisothermal transcription, which produce both single stranded RNA (ssRNA)and double stranded DNA (dsDNA) as the amplification products in a ratioof about 30 or 100 to 1, respectively.

[0042] B. Detection of Polymorphisms in Target DNA

[0043] The identity of bases occupying the polymorphic sites shown inTable 1 can be determined in an individual (e.g., a patient beinganalyzed) by several methods, which are described in turn.

[0044] 1. Allele-Specific Probes

[0045] The design and use of allele-specific probes for analyzingpolymorphisms is described by e.g., Saiki et al., Nature 324, 163-166(1986); Dattagupta, EP 235,726, Saiki, WO 89/11548. Allele-specificprobes can be designed that hybridize to a segment of target DNA fromone individual but do not hybridize to the corresponding segment fromanother individual due to the presence of different polymorphic forms inthe respective segments from the two individuals. Hybridizationconditions should be sufficiently stringent that there is a significantdifference in hybridization intensity between alleles, and preferably anessentially binary response, whereby a probe hybridizes to only one ofthe alleles. Some probes are designed to hybridize to a segment oftarget DNA such that the polymorphic site aligns with a central position(e.g., in a 15 mer at the 7 position; in a 16 mer, at either the 8 or 9position) of the probe. This design of probe achieves gooddiscrimination in hybridization between different allelic forms.

[0046] Allele-specific probes are often used in pairs, one member of apair showing a perfect match to a reference form of a target sequenceand the other member showing a perfect match to a variant form. Severalpairs of probes can then be immobilized on the same support forsimultaneous analysis of multiple polymorphisms within the same targetsequence.

[0047] 2. Tiling Arrays

[0048] The polymorphisms can also be identified by hybridization tonucleic acid arrays, some example of which are described by WO 95/11995(incorporated by reference in its entirety for all purposes). One formof such arrays is described in the Examples section in connection withde novo identification of polymorphisms. The same array or a differentarray can be used for analysis of characterized polymorphisms. WO95/11995 also describes subarrays that are optimized for detection of avariant forms of a precharacterized polymorphism. Such a subarraycontains probes designed to be complementary to a second referencesequence, which is an allelic variant of the first reference sequence.The second group of probes is designed by the same principles asdescribed in the Examples except that the probes exhibit complementarilyto the second reference sequence. The inclusion of a second group (orfurther groups) can be particular useful for analyzing shortsubsequences of the primary reference sequence in which multiplemutations are expected to occur within a short distance commensuratewith the length of the probes (i.e., two or more mutations within 9 to21 bases).

[0049] 3. Allele-Specific Primers

[0050] An allele-specific primer hybridizes to a site on target DNAoverlapping a polymorphism and only primes amplification of an allelicform to which the primer exhibits perfect complementarily. See Gibbs,Nucleic Acid Res. 17, 2427-2448 (1989). This primer is used inconjunction with a second primer which hybridizes at a distal site.Amplification proceeds from the two primers leading to a detectableproduct signifying the particular allelic form is present. A control isusually performed with a second pair of primers, one of which shows asingle base mismatch at the polymorphic site and the other of whichexhibits perfect complementarily to a distal site. The single-basemismatch prevents amplification and no detectable product is formed. Themethod works best when the mismatch is included in the 3′-most positionof the oligonucleotide aligned with the polymorphism because thisposition is most destabilizing to elongation from the primer. See, e.g.,WO 93/22456.

[0051] 4. Direct-Sequencing

[0052] The direct analysis of the sequence of polymorphisms of thepresent invention can be accomplished using either the dideoxy-chaintermination method or the Maxam-Gilbert method (see Sambrook et al.,Molecular Cloning, A Laboratory Manual (2nd Ed., CSHP, New York 1989);Zyskind et al., Recombinant DNA Laboratory Manual, (Acad. Press, 1988)).

[0053] 5. Denaturing Gradient Gel Electrophoresis

[0054] Amplification products generated using the polymerase chainreaction can be analyzed by the use of denaturing gradient gelelectrophoresis. Different alleles can be identified based on thedifferent sequence-dependent melting properties and electrophoreticmigration of DNA in solution. Erlich, ed., PCR Technology, Principlesand Applications for DNA Amplification, (W. H. Freeman and Co, New York,1992), Chapter 7.

[0055] 6. Single-Strand Conformation Polymorphism Analysis

[0056] Alleles of target sequences can be differentiated usingsingle-strand conformation polymorphism analysis, which identifies basedifferences by alteration in electrophoretic migration of singlestranded PCR products, as described in Orita et al., Proc. Nat. Acad.Sci. 86, 2766-2770 (1989). Amplified PCR products can be generated asdescribed above, and heated or otherwise denatured, to form singlestranded amplification products. Single-stranded nucleic acids mayrefold or form secondary structures which are partially dependent on thebase sequence. The different electrophoretic mobilities ofsingle-stranded amplification products can be related to base-sequencedifference between alleles of target sequences.

[0057] III. Methods of Use

[0058] After determining polymorphic form(s) present in an individual atone or more polymorphic sites, this information can be used in a numberof methods.

[0059] A. Association Studies with Hypertension

[0060] The polymorphisms of the invention may contribute to thephenotype of an organism in different ways. Some polymorphisms occurwithin a protein coding sequence and contribute to phenotype byaffecting protein structure. The effect may be neutral, beneficial ordetrimental, or both beneficial and detrimental, depending on thecircumstances. By analogy, a heterozygous sickle cell mutation confersresistance to malaria, but a homozygous sickle cell mutation is usuallylethal. Other polymorphisms occur in noncoding regions but may exertphenotypic effects indirectly via influence on replication,transcription, and translation. A single polymorphism may affect morethan one phenotypic trait. Likewise, a single phenotypic trait may beaffected by polymorphisms in different genes. Further, somepolymorphisms predispose an individual to a distinct mutation that iscausally related to a certain phenotype.

[0061] The polymorphism shown in Table 1 are analyzed for a correlationwith hypertension, the metabolic processes that lead to hypertension,and response to drugs used to treat hypertension. For purposes of thesestudies, hypertension can be defined as a dichotomous trait (e.g.,diastolic blood pressure greater than 90 mm Hg), as a continuous scaleof increasing severity based on blood pressure values, or as severalintermediate phenotypes. Because it is likely that the causation ofhypertension in the population is heterogenous, use of intermediatephenotypes can increase the strength of correlations identified. Someuseful subtypes for association studies are mendelian forms of humanhypertension, forms characterized by increased erythrocytesodium-lithium countertransport, forms characterized by altered urinarykallikrein levels, and forms characterized by sensitivity of bloodpressure to increases or decreases in sodium intake.

[0062] Correlation is performed for a population of individuals who havebeen tested for the presence or absence of hypertension or anintermediate phenotype and for one or polymorphic markers. To performsuch analysis, the presence or absence of a set of polymorphic forms(i.e. a polymorphic set) is determined for a set of the individuals,some of whom exhibit a particular trait, and some of which exhibit lackof the trait. The alleles of each polymorphism of the set are thenreviewed to determine whether the presence or absence of a particularallele is associated with the trait of interest. Correlation can beperformed by standard statistical methods such as a κ-squared test andstatistically significant correlations between polymorphic form(s) andphenotypic characteristics are noted. For example, it might be foundthat the presence of allele A1 at polymorphism A correlates withhypertension as a dichotomous trait. As a further example, it might befound that the combined presence of allele A1 at polymorphism A andallele B1 at polymorphism B correlates with increased erythrocyte sodiumlithium counter transport, an intermediate phenotype in development ofhypertension.

[0063] B. Diagnosis of Hypertension

[0064] Polymorphic forms that correlate with hypertension orintermediate phenotypes are useful in diagnosing hypertension orsusceptibility thereto. Combined detection of several such polymorphicforms (for example, 2, 5, 10 or 20 of the polymorphisms listed inTable 1) typically increases the probability of an accurate diagnosis.For example, the presence of a single polymorphic form known tocorrelate with hypertension might indicate a probability of 20% that anindividual has or is susceptible to hypertension, whereas detection offive polymorphic forms, each of which correlates with hypertension,might indicate a probability of 80% that an individual has or issusceptible to hypertension. Analysis of the polymorphisms of theinvention can be combined with that of other polymorphisms or other riskfactors of hypertension, such as family history or obesity, as well asmeasurements of blood pressure.

[0065] Patients diagnosed with hypertension can be treated withconventional therapies and/or can be counselled to undertake remediallife style changes, such as a low fat, low salt diet or more exercise.Conventional therapies include diuretics (e.g., thiazides), which lowerblood pressure by depleting the body of sodium and reducing bloodvolume; sympathoplegic agents (e.g., methyldopa and clonidine), whichlower blood pressure by reducing peripheral vascular resistance,inhibiting cardiac function and increasing venous pooling in capacitancevessels; direct vasodilators (e.g., hydralazine, minoxidil,, diazoxideand sodium nitroprusside), which reduce pressure by relaxing vascularsmooth muscle; agents that block production or action of angiotensin(e.g., captopril, enalapril and lisinopril), and thereby reduceperipheral vascular resistance; and adrenergic neuron blocking agents(e.g., guanethidine, reserpine, propranolol) which prevent release ofnorepinephrine. See, e.g., Basic and Clinical Pharmacology (Ed. Katzung,Appleton & Lange, CT, 1989).

[0066] C. Drug Screening

[0067] The polymorphism(s) showing the strongest correlation withhypertension within a given gene are likely to have a causative role inhypertension. Such a role can be confirmed by producing a transgenicanimal expressing a human gene bearing such a polymorphism anddetermining whether the animal develops hypertension. Polymorphisms incoding regions that result in amino acid changes usually causehypertension by decreasing, increasing or otherwise altering theactivity of the protein encoded by the gene in which the polymorphismoccurs. Polymorphisms in coding regions that introduce stop codonsusually cause hypertension by reducing (heterozygote) or eliminating(homozygote) functional protein produced by the gene. Occasionally, stopcodons result in production of a truncated peptide with aberrantactivities relative to the full-length protein. Polymorphisms inregulatory regions typically cause hypertension by causing increased ordecreased expression of the protein encoded by the gene in which thepolymorphism occurs. Polymorphisms in intronic sequences can causehypertension either through the same mechanism as polymorphisms inregulatory sequences or by causing altered spliced patterns resulting inan altered protein. For example, alternative splice patterns have beenreported for the human angiotensin II receptor gene (Curnow et al.,Molecular Endocrinology 9, 1250-1262 (1995)).

[0068] The precise role of polymorphisms in hypertension can beelucidated by several means. Alterations in expression levels of aprotein (e.g., sodium-calcium ion channel) can be determined bymeasuring protein levels in samples groups of persons characterized ashaving or not having hypertension (or intermediate phenotypes).Alterations in enzyme activity (e.g., renin), can similarly be detectedby assaying for enzyme activity in samples from the above groups ofpersons. Alterations in receptor transducing activity (e.g., angiotensinII receptor, β-3-adrenergic receptor or bradykinin receptor B2) can bedetected by comparing receptor ligand binding, either in vitro or in acellular expression system.

[0069] Having identified certain polymorphisms as having causative rolesin hypertension, and having elucidated at least in general terms whethersuch polymorphisms increase or decrease the activity or expression levelof associated proteins, customized therapies can be devised for classesof patients with different genetic subtypes of hypertension. Forexample, if a polymorphism in a given protein causes hypertension byincreasing the expression level or activity of the protein, hypertensionassociated with the polymorphism can be treated by administering anantagonist of the protein. If a polymorphism in a given protein causeshypertension by decreasing the expression level or activity of aprotein, the form of hypertension associated with the polymorphism canbe treated by administering the protein itself, a nucleic acid encodingthe protein that can be expressed in a patient, or an analog or agonistof the protein.

[0070] Agonists, antagonists can be obtained by producing and screeninglarge combinatorial libraries. Combinatorial libraries can be producedfor many types of compound that can be synthesized in a step by stepfashion. Such compounds include polypeptides, beta-turn mimetics,polysaccharides, phospholipids, hormones, prostaglandins, steroids,aromatic compounds, heterocyclic compounds, benzodiazepines, oligomericN-substituted glycines and oligocarbamates. Large combinatoriallibraries of the compounds can be constructed by the encoded syntheticlibraries (ESL) method described in Affymax, WO 95/12608, Affymax, WO93/06121, Columbia University, WO 94/08051, Pharmacopeia, WO 95/35503and Scripps, WO 95/30642 (each of which is incorporated by reference forall purposes). Peptide libraries can also be generated by phage displaymethods. See, e.g., Devlin, WO 91/18980. The libraries of compounds canbe initially screened for specific binding to the protein for whichagonists or antagonists are to be identified, or to its natural bindingpartner. Preferred agents bind with a Kd<μM. For example, for receptorligand combinations, the assay can be performed using cloned receptorimmobilized to a support such as a microtiter well and binding ofcompounds can be measured in competition with ligand to the receptor.Agonist or antagonist activity can then be assayed using a cellularreporter system or a transgenic animal model.

[0071] The polymorphisms of the invention are also useful for conductingclinical trials of drug candidates for hypertension. Such trials areperformed on treated or control populations having similar or identicalpolymorphic profiles at a defined collection of polymorphic sites. Useof genetically matched populations eliminates or reduces variation intreatment outcome due to genetic factors, leading to a more accurateassessment of the efficacy of a potential drug.

[0072] D. Other Diseases

[0073] The polymorphisms in Table 1 can also be tested for associationwith other disease that have known but hitherto unmapped geneticcomponents (e.g., agammaglobulinemia, diabetes insipidus, Lesch-Nyhansyndrome, muscular dystrophy, Wiskott-Aldrich syndrome, Fabry's disease,familial hypercholesterolemia, polycystic kidney disease, hereditaryspherocytosis, von Willebrand's disease, tuberous sclerosis, hereditaryhemorrhagica telangiectasia, familial colonic polyposis, Ehlers-Danlossyndrome, osteogenesis imperfecta, and acute intermittent porphyria).Phenotypic traits also include symptoms of, or susceptibility to,multifactorial diseases of which a component is or may be genetic, suchas autoimmune diseases, inflammation, cancer, diseases of the nervoussystem, and infection by pathogenic microorganisms. Some examples ofautoimmune diseases include rheumatoid arthritis, multiple sclerosis,diabetes (insulin-dependent and non-independent), systemic lupuserythematosus and Graves disease. Some examples of cancers includecancers of the bladder, brain, breast, colon, esophagus, kidney,leukemia, liver, lung, oral cavity, ovary, pancreas, prostate, skin,stomach and uterus. Phenotypic traits also include characteristics suchas longevity, appearance (e.g., baldness, obesity), strength, speed,endurance, fertility, and susceptibility or receptivity to particulardrugs or therapeutic treatments.

[0074] Such correlations can be exploited in several ways. In the caseof a strong correlation between a set of one or more polymorphic formsand a disease for which treatment is available, detection of thepolymorphic form set in a human or animal patient may justify immediateadministration of treatment, or at least the institution of regularmonitoring of the patient. Detection of a polymorphic form correlatedwith serious disease in a couple contemplating a family may also bevaluable to the couple in their reproductive decisions. For example, thefemale partner might elect to undergo in vitro fertilization to avoidthe possibility of transmitting such a polymorphism from her husband toher offspring. In the case of a weaker, but still statisticallysignificant correlation between a polymorphic set and human disease,immediate therapeutic intervention or monitoring may not be justified.Nevertheless, the patient can be motivated to begin simple life-stylechanges (e.g., diet, exercise) that can be accomplished at little costto the patient but confer potential benefits in reducing the risk ofconditions to which the patient may have increased susceptibility byvirtue of variant alleles. Identification of a polymorphic set in apatient correlated with enhanced receptiveness to one of severaltreatment regimes for a disease indicates that this treatment regimeshould be followed.

[0075] E. Forensics

[0076] Determination of which polymorphic forms occupy a set ofpolymorphic sites in an individual identifies a set of polymorphic formsthat distinguishes the individual. See generally National ResearchCouncil, The Evaluation of Forensic DNA Evidence (Eds. Pollard et al.,National Academy Press, DC, 1996). The more sites that are analyzed thelower the probability that the set of polymorphic forms in oneindividual is the same as that in an unrelated individual. Preferably,if multiple sites are analyzed, the sites are unlinked. Thus,polymorphisms of the invention are often used in conjunction withpolymorphisms in distal genes. Preferred polymorphisms for use inforensics are diallelic because the population frequencies of twopolymorphic forms can usually be determined with greater accuracy thanthose of multiple polymorphic forms at multi-allelic loci.

[0077] The capacity to identify a distinguishing or unique set offorensic markers in an individual is useful for forensic analysis. Forexample, one can determine whether a blood sample from a suspect matchesa blood or other tissue sample from a crime scene by determining whetherthe set of polymorphic forms occupying selected polymorphic sites is thesame in the suspect and the sample. If the set of polymorphic markersdoes not match between a suspect and a sample, it can be concluded(barring experimental error) that the suspect was not the source of thesample. If the set of markers does match, one can conclude that the DNAfrom the suspect is consistent with that found at the crime scene. Iffrequencies of the polymorphic forms at the loci tested have beendetermined (e.g., by analysis of a suitable population of individuals),one can perform a statistical analysis to determine the probability thata match of suspect and crime scene sample would occur by chance.

[0078] p(ID) is the probability that two random individuals have thesame polymorphic or allelic form at a given polymorphic site. Indiallelic loci, four genotypes are possible: AA, AB, BA, and BB. Ifalleles A and B occur in a haploid genome of the organism withfrequencies x and y, the probability of each genotype in a diploidorganism are (see WO 95/12607):

Homozygote: p(AA)=x2

Homozygote: p(BB)=y2=(1−x)2

Single Heterozygote: p(AB)=p(BA)=xy=x(1−x)

Both Heterozygotes: p(AB+BA)=2xy=2x(1−x)

[0079] The probability of identity at one locus (i.e, the probabilitythat two individuals, picked at random from a population will haveidentical polymorphic forms at a given locus) is given by the equation:

p(ID)=(x2)2+(2xy)2+(y2)2.

[0080] These calculations can be extended for any number of polymorphicforms at a given locus. For example, the probability of identity p(ID)for a 3-allele system where the alleles have the frequencies in thepopulation of x, y and z, respectively, is equal to the sum of thesquares of the genotype frequencies:

p(ID)=x4+(2xy)2+(2yz)2+(2xz)2+z4+y4

[0081] In a locus of n alleles, the appropriate binomial expansion isused to calculate p(ID) and p(exc).

[0082] The cumulative probability of identity (cum p(ID)) for each ofmultiple unlinked loci is determined by multiplying the probabilitiesprovided by each locus.

cum p(ID)=p(ID1)p(ID2)p(ID3) . . . p(IDn)

[0083] The cumulative probability of non-identity for n loci (i.e. theprobability that two random individuals will be different at 1 or moreloci) is given by the equation:

cum p(nonID)=1−cum p(ID).

[0084] If several polymorphic loci are tested, the cumulativeprobability of non-identity for random individuals becomes very high(e.g., one billion to one). Such probabilities can be taken into accounttogether with other evidence in determining the guilt or innocence ofthe suspect.

[0085] F. Paternity Testing

[0086] The object of paternity testing is usually to determine whether amale is the father of a child. In most cases, the mother of the child isknown and thus, the mother's contribution to the child's genotype can betraced. Paternity testing investigates whether the part of the child'sgenotype not attributable to the mother is consistent with that of theputative father. Paternity testing can be performed by analyzing sets ofpolymorphisms in the putative father and the child.

[0087] If the set of polymorphisms in the child attributable to thefather does not match the putative father, it can be concluded, barringexperimental error, that the putative father is not the real father. Ifthe set of polymorphisms in the child attributable to the father doesmatch the set of polymorphisms of the putative father, a statisticalcalculation can be performed to determine the probability ofcoincidental match.

[0088] The probability of parentage exclusion (representing theprobability that a random male will have a polymorphic form at a givenpolymorphic site that makes him incompatible as the father) is given bythe equation (see WO 95/12607):

p(exc)=xy(1−xy)

[0089] where x and y are the population frequencies of alleles A and Bof a diallelic polymorphic site.

(At a triallelic site p(exc)=xy(1−xy)+yz(1−yz)+xz(1−xz)+3xyz(1−xyz))),

[0090] where x, y and z and the respective population frequencies ofalleles A, B and C).

[0091] The probability of non-exclusion is

p(non-exc)=1−p(exc)

[0092] The cumulative probability of non-exclusion (representing thevalue obtained when n loci are used) is thus:

cum p(non-exc)=p(non-exc1)p(non-exc2)p(non-exc3) . . . p(non-excn)

[0093] The cumulative probability of exclusion for n loci (representingthe probability that a random male will be excluded)

cum p(exc)=1−cum p(non-exc).

[0094] If several polymorphic loci are included in the analysis, thecumulative probability of exclusion of a random male is very high. Thisprobability can be taken into account in assessing the liability of aputative father whose polymorphic marker set matches the child'spolymorphic marker set attributable to his/her father.

[0095] G. Genetic Mapping of Phenotypic Traits

[0096] The polymorphisms shown in table 1 can also be used to establishphysical linkage between a genetic locus associated with a trait ofinterest and polymorphic markers that are not associated with the trait,but are in physical proximity with the genetic locus responsible for thetrait and co-segregate with it. Such analysis is useful for mapping agenetic locus associated with a phenotypic trait to a chromosomalposition, and thereby cloning gene(s) responsible for the trait. SeeLander et al., Proc. Natl. Acad. Sci. (USA) 83, 7353-7357 (1986); Landeret al., Proc. Natl. Acad. Sci. (USA) 84, 2363-2367 (1987); Donis-Kelleret al., Cell 51, 319-337 (1987); Lander et al., Genetics 121, 185-199(1989)). Genes localized by linkage can be cloned by a process known asdirectional cloning. See Wainwright, Med. J. Australia 159, 170-174(1993); Collins, Nature Genetics 1, 3-6 (1992) (each of which isincorporated by reference in its entirety for all purposes).

[0097] Linkage studies are typically performed on members of a family.Available members of the family are characterized for the presence orabsence of a phenotypic trait and for a set of polymorphic markers. Thedistribution of polymorphic markers in an informative meiosis is thenanalyzed to determine which polymorphic markers co-segregate with aphenotypic trait. See, e.g., Kerem et al., Science 245, 1073-1080(1989); Monaco et al., Nature 316, 842 (1985); Yamoka et al., Neurology40, 222-226 (1990); Rossiter et al., FASEB Journal 5, 21-27 (1991).

[0098] Linkage is analyzed by calculation of LOD (log of the odds)values. A lod value is the relative likelihood of obtaining observedsegregation data for a marker and a genetic locus when the two arelocated at a recombination fraction θ, versus the situation in which thetwo are not linked, and thus segregating independently (Thompson &Thompson, Genetics in Medicine (5th ed, W. B. Saunders Company,Philadelphia, 1991); Strachan, “Mapping the human genome” in The HumanGenome (BIOS Scientific Publishers Ltd, Oxford), Chapter 4). A series oflikelihood ratios are calculated at various recombination fractions (θ),ranging from θ=0.0 (coincident loci) to θ=0.50 (unlinked). Thus, thelikelihood at a given value of θ is: probability of data if loci linkedat θ to probability of data if loci unlinked. The computed likelihoodsare usually expressed as the log10 of this ratio (i.e., a lod score).For example, a lod score of 3 indicates 1000:1 odds against an apparentobserved linkage being a coincidence. The use of logarithms allows datacollected from different families to be combined by simple addition.Computer programs are available for the calculation of lod scores fordiffering values of θ (e.g., LIPED, MLINK (Lathrop, Proc. Nat. Acad.Sci. (USA) 81, 3443-3446 (1984)). For any particular lod score, arecombination fraction may be determined from mathematical tables. SeeSmith et al., Mathematical tables for research workers in human genetics(Churchill, London, 1961); Smith, Ann. Hum. Genet. 32, 127-150 (1968).The value of θ at which the lod score is the highest is considered to bethe best estimate of the recombination fraction. Positive lod scorevalues suggest that the two loci are linked, whereas negative valuessuggest that linkage is less likely (at that value of θ) than thepossibility that the two loci are unlinked. By convention, a combinedlod score of +3 or greater (equivalent to greater than 1000:1 odds infavor of linkage) is considered definitive evidence that two loci arelinked. Similarly, by convention, a negative lod score of −2 or less istaken as definitive evidence against linkage of the two loci beingcompared. Negative linkage data are useful in excluding a chromosome ora segment thereof from consideration. The search focuses on theremaining non-excluded chromosomal locations.

[0099] IV. Modified Polypeptides and Gene Sequences

[0100] The invention further provides variant forms of nucleic acids andcorresponding proteins. The nucleic acids comprise one of the sequencesdescribed in Table 1, column 8, in which the polymorphic position isoccupied by an alternative base for that position. Some nucleic acidencode full-length variant forms of proteins. Similarly, variantproteins have the prototypical amino acid sequences of encoded bynucleic acid sequence shown in Table 1, column 8, (read so as to bein-frame with the full-length coding sequence of which it is acomponent) except at an amino acid encoded by a codon including one ofthe polymorphic positions shown in the Table. That position is occupiedby the amino acid coded by the corresponding codon in the alternativeforms shown in the Table.

[0101] Variant genes can be expressed in an expression vector in which avariant gene is operably linked to a native or other promoter. Usually,the promoter is a eukaryotic promoter for expression in a mammaliancell. The transcription regulation sequences typically include aheterologous promoter and optionally an enhancer which is recognized bythe host. The selection of an appropriate promoter, for example trp,lac, phage promoters, glycolytic enzyme promoters and tRNA promoters,depends on the host selected. Commercially available expression vectorscan be used. Vectors can include host-recognized replication systems,amplifiable genes, selectable markers, host sequences useful forinsertion into the host genome, and the like.

[0102] The means of introducing the expression construct into a hostcell varies depending upon the particular construction and the targethost. Suitable means include fusion, conjugation, transfection,transduction, electroporation or injection, as described in Sambrook,supra. A wide variety of host cells can be employed for expression ofthe variant gene, both prokaryotic and eukaryotic. Suitable host cellsinclude bacteria such as E. coli, yeast, filamentous fungi, insectcells, mammalian cells, typically immortalized, e.g., mouse, CHO, humanand monkey cell lines and derivatives thereof. Preferred host cells areable to process the variant gene product to produce an appropriatemature polypeptide. Processing includes glycosylation, ubiquitination,disulfide bond formation, general post-translational modification, andthe like.

[0103] The protein may be isolated by conventional means of proteinbiochemistry and purification to obtain a substantially pure product,i.e., 80, 95 or 99% free of cell component contaminants, as described inJacoby, Methods in Enzymology Volume 104, Academic Press, New York(1984); Scopes, Protein Purification, Principles and Practice, 2ndEdition, Springer-Verlag, New York (1987); and Deutscher (ed), Guide toProtein Purification, Methods in Enzymology, Vol. 182 (1990). If theprotein is secreted, it can be isolated from the supernatant in whichthe host cell is grown. If not secreted, the protein can be isolatedfrom a lysate of the host cells.

[0104] The invention further provides transgenic nonhuman animalscapable of expressing an exogenous variant gene and/or having one orboth alleles of an endogenous variant gene inactivated. Expression of anexogenous variant gene is usually achieved by operably linking the geneto a promoter and optionally an enhancer, and microinjecting theconstruct into a zygote. See Hogan et al., “Manipulating the MouseEmbryo, A Laboratory Manual,” Cold Spring Harbor Laboratory.Inactivation of endogenous variant genes can be achieved by forming atransgene in which a cloned variant gene is inactivated by insertion ofa positive selection marker. See Capecchi, Science 244, 1288-1292(1989). The transgene is then introduced into an embryonic stem cell,where it undergoes homologous recombination with an endogenous variantgene. Mice and other rodents are preferred animals. Such animals provideuseful drug screening systems.

[0105] In addition to substantially full-length polypeptides expressedby variant genes, the present invention includes biologically activefragments of the polypeptides, or analogs thereof, including organicmolecules which simulate the interactions of the peptides. Biologicallyactive fragments include any portion of the full-length polypeptidewhich confers a biological function on the variant gene product,including ligand binding, and antibody binding. Ligand binding includesbinding by nucleic acids, proteins or polypeptides, small biologicallyactive molecules, or large cellular structures.

[0106] Polyclonal and/or monoclonal antibodies that specifically bind tovariant gene products but not to corresponding prototypical geneproducts are also provided. Antibodies can be made by injecting mice orother animals with the variant gene product or synthetic peptidefragments thereof. Monoclonal antibodies are screened as are described,for example, in Harlow & Lane, Antibodies, A Laboratory Manual, ColdSpring Harbor Press, New York (1988); Goding, Monoclonal antibodies,Principles and Practice (2d ed.) Academic Press, New York (1986).Monoclonal antibodies are tested for specific immunoreactivity with avariant gene product and lack of immunoreactivity to the correspondingprototypical gene product. These antibodies are useful in diagnosticassays for detection of the variant form, or as an active ingredient ina pharmaceutical composition.

[0107] V. Kits

[0108] The invention further provides kits comprising at least oneallele-specific oligonucleotide as described above. Often, the kitscontain one or more pairs of allele-specific oligonucleotideshybridizing to different forms of a polymorphism. In some kits, theallele-specific oligonucleotides are provided immobilized to asubstrate. For example, the same substrate can comprise allele-specificoligonucleotide probes for detecting at least 10, 100 or all of thepolymorphisms shown in Table 1. Optional additional components of thekit include, for example, restriction enzymes, reverse-transcriptase orpolymerase, the substrate nucleoside triphosphates, means used to label(for example, an avidin-enzyme conjugate and enzyme substrate andchromogen if the label is biotin), and the appropriate buffers forreverse transcription, PCR, or hybridization reactions. Usually, the kitalso contains instructions for carrying out the methods.

[0109] VI. Computer Systems For Storing Polymorphism Data

[0110]FIG. 1A depicts a block diagram of a computer system 10 suitablefor implementing the present invention. Computer system 10 includes abus 12 which interconnects major subsystems such as a central processor14, a system memory 16 (typically RAM), an input/output (I/O) controller18, an external device such as a display screen 24 via a display adapter26, serial ports 28 and 30, a keyboard 32, a fixed disk drive 34 via astorage interface 35 and a floppy disk drive 36 operative to receive afloppy disk 38, and a CD-ROM (or DVD-ROM) device 40 operative to receivea CD-ROM 42. Many other devices can be connected such as a user pointingdevice, e.g., a mouse 44 connected via serial port 28 and a networkinterface 46 connected via serial port 30.

[0111] Many other devices or subsystems (not shown) may be connected ina similar manner. Also, it is not necessary for all of the devices shownin FIG. 1A to be present to practice the present invention, as discussedbelow. The devices and subsystems may be interconnected in differentways from that shown in FIG. 1A. The operation of a computer system suchas that shown in FIG. 1A is well known. Databases storing polymorphisminformation according to the present invention can be stored, e.g., insystem memory 16 or on storage media such as fixed disk 34, floppy disk38, or CD-ROM 42. An application program to access such databases can beoperably disposed in system memory 16 or sorted on storage media such asfixed disk 34, floppy disk 38, or CD-ROM 42.

[0112]FIG. 1B depicts the interconnection of computer system 10 toremote computers 48, 50, and 52. FIG. 1B depicts a network 54interconnecting remote servers 48, 50, and 52. Network interface 46provides the connection from client computer system 10 to network 54.Network 54 can be, e.g., the Internet. Protocols for exchanging data viathe Internet and other networks are well known. Information identifyingthe polymorphisms described herein can be transmitted across network 54embedded in signals capable of traversing the physical media employed bynetwork 54.

[0113] Information identifying polymorphisms shown in Table 1 isrepresented in records, which optionally, are subdivided into fields.Each record stores information relating to a different polymorphisms inTable 1. Collectively, the records can store information relating to allof the polymorphisms in Table 1, or any subset thereof, such as 5, 10,50, or 100 polymorphisms from Table 1. In some databases, theinformation identifies a base occupying a polymorphic position and thelocation of the polymorphic position. The base can be represented as asingle letter code (i.e., A, C, G or T/U) present in a polymorphic formother than that in the reference allele. Alternatively, the baseoccupying a polymorphic site can be represented in IUPAC ambiguity codeas shown in Table 1. The location of a polymorphic site can beidentified as its position within one of the sequences shown in Table 1.For example, in the first sequence shown in Table 1, the polymorphicsite occupies the 15th base. The position can also be identified byreference to, for example, a chromosome, and distance from known markerswithin the chromosome. In other databases, information identifying apolymorphism contains sequences of 10-100 bases shown in Table 1 or thecomplements thereof, including a polymorphic site. Preferably, suchinformation records at least 10, 15, 20, or 30 contiguous bases ofsequences including a polymorphic site.

[0114] From the foregoing, it is apparent that the invention includes anumber of general uses that can be expressed concisely as follows. Theinvention provides for the use of any of the nucleic acid segmentsdescribed above in the diagnosis or monitoring of diseases, particularlyhypertension. The invention further provides for the use of any of thenucleic acid segments in the manufacture of a medicament for thetreatment or prophylaxis of such diseases. The invention furtherprovides for the use of any of the DNA segments as a pharmaceutical.

[0115] All publications and patent applications cited above areincorporated by reference in their entirety for all purposes to the sameextent as if each individual publication or patent application werespecifically and individually indicated to be so incorporated byreference. Although the present invention has been described in somedetail by way of illustration and example for purposes of clarity andunderstanding, it will be apparent that certain changes andmodifications may be practiced within the scope of the appended claims.TABLE 1 Heteroz Type of Alt Base Ref Alt ygosity Ref Alt amino acid Refamino amino Gene/Exon Position Allele Freq (P) Allele Freq (Q) (H)Sequence Tag Codon Codon Change acid acid AADDEX1 305 G 0.98 A 0.03 0.05ACGGGGGCGGAGCCRGAGCCGGAGCCGAC . . Other 5′UTR . AADDEX10 246 G 0.86 T0.14 0.23 AAGCTTCCGAGGAAKGGCAGAATGGAAGC GGG TGG Nonsynonymous Gly TrpAADDEX12 43 A 0.94 T 0.06 0.11 GATCCGAGAGCAGAWTTTACAGGACATTA AAT ATTNonsynonymous Asn Ile AADDEX13 173 C 0.70 G 0.30 0.42GAAGCAGAAGGGCTSTGAAGGTGAGTGCT TCT TGT Nonsynonymous Ser Cys AADDEX15 74C 0.73 T 0.27 0.40 CCTAGTAAGTACCGYGCTGCCTCCGCTCT . . Other IntronAADDEX16 1071 G 0.99 A 0.01 0.02 ATTCCTGTCATAGGRAAGGTATATCAGGA . . Other3′UTR AADDEX16 1321 C 0.98 T 0.02 0.04 GCCCTGGGGCCCCTYGACATCACCGTCAT . .Other 3′UTR AADDEX16 1328 A 0.91 G 0.09 0.17GGCCCCTCGACATCRCCGTCATTGATGGA . . Other 3′UTR AADDEX16 1478 A 0.89 G0.11 0.19 CAGCCTGACTAGGTRCAGGCAAGCTTGTG . . Other 3′UTR AADDEX16 691 C0.99 G 0.01 0.02 CAGCTTTGGCTGCASGTCACCCTCCTGAG . . Other 3′UTR AADDEX16995 C 0.94 T 0.06 0.11 TATGCATGTCTGACYGACGATCCCTCGAC . . Other 3′UTRAADDEX2 31 A 0.98 G 0.03 0.05 TTTGATTCTGTAGGRACCTAGAAAGATTG . . Other5′UTR AADDEX7 96 T 0.98 A 0.02 0.04 TTGGAGAAGTGGCTWATCATGACTACCAT TATAAT Nonsynonymous Tyr Asn AADDEX9 173 A 0.93 T 0.07 0.13ATTGGTGAGCAGGAWTTTGAAGCCCTCAT GAA GAT Nonsynonymous Glu Asp ACEEX13 151T 0.75 C 0.25 0.38 CCAGCCAGGAGGCAYCCCAACAGGTGACA TCT CCT NonsynonymousSer Pro ACEEX13 202 A 0.75 C 0.25 0.38 AGGCAACAACCAGCRGCCAGACAACCACC AGCGGC Nonsynonymous Ser Gly ACEEX15 144 G 0.80 A 0.20 0.32CTAGAACGGGCAGCRCTGCCTGCCCAGGA GCG GCA Synonymous Ala Ala ACEEX17 19 C0.69 A 0.31 0.43 CTCAAGCCATTCAAMCCCCTACCAGATCT . . Other Intron ACEEX18130 C 0.95 G 0.05 0.09 CAGCCACTCTACCTSAACCTGCATGCCTA CTC CTG SynonymousLeu Leu ACEEX21 150 T 0.98 C 0.03 0.05 CTTCCATGAGGCCAYTGGGGACGTGCTAG ATTACT Nonsynonymous Ile Thr ACEEX22 19 T 0.99 G 0.01 0.03AGCATGACATCAACKTTCTGATGAAGATG TTT GTT Nonsynonymous Phe Val ACEEX24 118C 0.95 T 0.05 0.10 CAGTCCAAGGAGGCYGGGCAGCGCCTGGG GCC GCT Synonymous AlaAla ACEEX24 16 T 0.57 C 0.43 0.49 TGCTCCAGGTACTTYGTCAGCTTCATCAT TTT TTCSynonymous Phe Phe ACEEX26 154 G 0.98 A 0.03 0.05GGGCCTCAGCCAGCRGCTCTTCAGCATCC CGG CAG Nonsynonymous Arg Gln ACEEX26 174C 0.90 A 0.10 0.18 TCAGCATCCGCCACMGCAGCCTCCACCGG CGC AGC NonsynonymousArg Ser ACEEX26 205 A 0.98 C 0.02 0.03 CTCCCACGGGCCCCMGTTCGGCTCCGAGG CAGCCG Nonsynonymous Gln Pro ACEEX26 224 G 0.94 A 0.06 0.11GGCTCCGAGGTGGARCTGAGACACTCCTG GAG GAA Synonymous Glu Glu ADDBEX10 81 G0.98 T 0.03 0.05 CTCCTGGAGCAGGAKAAGCACCGGCCCCA GAG GAT Nonsynonymous GluAsp ADDBEX15 68 G 0.99 A 0.01 0.03 GCTCTGGTCCGGCCRTGTGCGAGTTCTTC CCG CCASynonymous Pro Pro ADDBEX15 85 C 0.90 T 0.10 0.18TGCGAGTTCTTCAGYGTTGCCCTCCACAT GCG GTG Nonsynonymous Ala Val ADDBEX17 147C 0.98 A 0.02 0.04 GAGGAAATCCTCAGMAAAGGCCTGAGCCA AGC AGA NonsynonymousSer Arg ADDBEX3 138 G 0.89 A 0.11 0.19 GCTTCTCAGAGGACRACCCCGAGTACATG GACAAC Nonsynonymous Asp Asn ADDBEX4 134 C 0.99 G 0.01 0.02CATGGCCAGCACCTSCCACGCAGTCTTCC TCC TGC Nonsynonymous Ser Cys ADDBEX8 173A 0.96 G 0.04 0.07 CCACCTGCAAGGTTRGCTTAGCTCTTCTG . . Other IntronADDBEX9 69 T 0.99 C 0.01 0.02 GTAGAGGAGGCATTYTACAAGATCTTCCA TTT TTCSynonymous Phe Phe ADDG 2087 T 0.98 C 0.02 0.03TGACATTGCACATCYAAATACCACATTTA . . Other 3′UTR ADORA2AEX1 429 C 0.97 T0.03 0.07 GGTGTCACTGGCGGYGGCCGACATCGCAG GCG GTG Nonsynonymous Ala ValADORA2AEX2 1230 G 0.97 T 0.03 0.06 TGCAGAAGCATCTGKAAGCACCACCTTGT . .Other 3′UTR ADORA2AEX2596 G 0.97 A 0.03 0.06CCGCCAGACCTTCCRCAAGATCATTCGCA CGC CAC Nonsynonymous Arg HisADORA2AEX2741 C 0.92 T 0.08 0.15 GGAGTGTGGGCCAAYGGCAGTGCTCCCCA AAC AATSynonymous Asn Asn ADRB3EX1 1020 C 0.96 T 0.04 0.07GGCCCCGGTGGGGAYGTGCGCT ACG ATG Nonsynonymous Thr Met ADRB3EX1 1354 C0.89 T 0.11 0.20 TGCGCCGCCGCCCGYCCGGCCCTCTTCCC CGC CGT Synonymous ArgArg ADRB3EX1 1445 G 0.90 T 0.10 0.18 GGTAGGTAACCGGGKCAGAGGGACCGGCG . .Other Intron ADRB3EX1 44 A G GCTACTCCTCCCCCRAGAGCGGTGGCACC . . OtherIntron ADRB3EX2 301 G 0.96 C 0.04 0.08 GTGGTAGTGTCCAGSTGCCGTGGAGCAGC . .Other 3′UTR ADRB3EX2 408 C 0.80 T 0.20 0.32TGGTTCCATTCCTTYTGCCACCCAAACCC . . Other 3′UTR ADROMEX1 1197 C 0.98 T0.02 0.04 TGGGACGTCTGAGAYTTTCTCCTTCAAGT . . Other 5′UTR ADROMEX1 154 G0.98 T 0.02 0.05 ATGTTACCTTCCTTKCCTGACTCAAGGGT . . Other PromoterADROMEX1 723 G 0.97 T 0.03 0.06 GGGCTCTTGCTGTTYTTCGCCAGGAGGCT . . OtherPromoter ADROMEX1 981 G 0.99 A 0.01 0.03 GAGCAGGAGCGCGCRTGGCTGAGGAAAGA .. Other Promoter ADROMEX2 101 A 0.96 C 0.04 0.07TCGCTCGCCTTCCTMGGCGCTGACACCGC CTA CTC Synonymous Leu Leu ADROMEX3 81 C0.95 C 0.05 0.09 CTGCGGATGTCCAGSAGCTACCCCACCGG AGC AGG Nonsynonymous SerArg ADROMEX4 1033 T 0.95 C 0.05 0.09 ACCGAGTCTCTGTAYAATCTATTTACATA . .Other 3′UTR ADROMEX4 1292 A 0.98 G 0.02 0.05TGTCCTGGGTGCGARTCAGGGCTTCGCGG . . Other 3′UTR ADROMEX4 1389 T 0.97 C0.03 0.06 GCGAGCCTGGACTCYCGGGTTGCGCAACG . . Other 3′UTR ADROMEX4 388 G0.98 C 0.02 0.05 CAAGCATCCCGCTGSTGCCTCCCGGGACG . . Other 3′UTR ADROMEX4536 T 0.98 G 0.02 0.04 CGCTTCCTTAGCCTKGCTCAGGTGCAAGT . . Other 3′UTRADROMEX4 918 A 0.91 G 0.09 0.16 ATTTTAAOACGTGARTGTCTCAGCGAGGT . . Other3′UTR AEIEX1 298 G 0.95 A 0.05 0.10 GGGGCATGAGTCAGRGGTTTGCGAGCTGC . .Other Promoter AEIEX1 80 A 0.98 C 0.02 0.04TCAAACCTTCATCCMCAAAGGAAGAGTCA . . Other Promoter AE1EX10 77 G 0.99 A0.01 0.02 CGAGGGGAGCTGCTRCACTCCCTAGAGGG CTG CTA Synonymous Leu LeuAELEX11 181 C 0.95 T 0.05 0.10 GTCATCTTCATCTAYTTTGCTGCACTGTC TAC TATSynonymous Tyr Tyr AEIEX11 191 C 0.99 T 0.01 0.03TCTACTTTGCTGCAYTGTCACCCGCCATC CTG TTG Synonymous Leu Leu AEIEX11 228 A0.98 T 0.02 0.04 CGGCCTCCTGGGTCWGTGCCAATACCTGT . . Other Intron AEIEX1270 G 0.93 A 0.07 0.13 GTGTCGGAGCTGCTRATCTCCACTGCAGT CTG CTA SynonymousLeu Leu AEIEX12 71 A 0.96 T 0.04 0.07 TGTCGGAGCTGCTGWTCTCCACTGCAGTO ATCTTC Nonsynonymous Ile Phe AEIEX14 159 A 0.93 T 0.07 0.13CCTTCYFCTTTGCCWTGATGCTGCGCAAG ATG TTG Nonsynonymous Met Leu AEIEX15 107T 0.79 C 0.21 0.33 TTCTTCATTCAGGAYACCTACACCCAGGT GAT GAC Synonymous AspAsp AEIEX16 92 C 0.97 T 0.03 0.06 GGCTGGGTCATCCAYCCACTGGGCTTGCG CAC CATSynonymous His His AEIEX17 34 A 0.97 G 0.03 0.06CCTACAGTAGGCTGRTTGTCAGCAAACCT ATT GTT Nonsynonymous Ile Val AEIEX17 40 A0.99 G 0.01 0.02 GTAGGCTGATTGTCRGCAAACCTGAGCGC AGC GGC Nonsynonymous SerGly AEIEX17 72 C 0.94 T 0.06 0.11 ATGGTCAAGGGCTCYGGCTTCCACCTGGA TCC TCTSynonymous Ser Ser AEIEX19 132 G 0.96 A 0.04 0.07TGGCCCTGCCCTTCRTCCTCATCCTCACT COT CAT Nonsynonymous Arg His AEIEX19 43 G0.99 A 0.01 0.02 GGTGAAGACCTGGCRCATGCACTTATTCA CGC CAC Nonsynonymous ArgHis AEIEX20 1007 G 0.99 A 0.01 0.03 AATCAGTGGACTCCRAGGGGACTGAGACA . .Other 3UTR AEIEX20 1213 A 0.64 T 0.36 0.46 ATTTGAGAGCCATTWTCCTCAACTCCATC. . Other 3′UTR AEIEX20 1542 T 0.94 C 0.06 0.12AAAAATACAAAAATYAGCTGGGTGTCTCG . . Other 3′UTR AEIEX20 1628 G 0.95 C 0.050.10 CCCAGGAGGTGGAGSTTGCAGTGAGCCAA . . Other 3′UTR AEIEX20 1679 A 0.68 G0.32 0.44 CTGGGCAACAGAGCRAGACCCTGTCTCAA . . Other 3′UTR AEIEX20 379 G0.97 A 0.03 0.06 TCACTGGGGATCCCRTGCTGGAAGACTTA . . Other 3′UTR AEIEX20418 C 0.99 A 0.01 0.03 CTCCCTCTTCCCAGMACAGGCAGGGGTAG . . Other 3′UTRAEIEX20 991 G 0.99 A 0.01 0.02 TTACTGAGGGCCCCRGAATCAGTGGACTC . . Other3′UTR AEIEX4 17 C 0.98 T 0.03 0.05 CAATACTAACCGACYTCTGGTTTTCAGCT . .Other Intron AEIEX4 36 A 0.91 C 0.09 0.16 GTTTTCAGCTCACGMCACCGAGGCAACAGGAC GCC Nonsynonymous Asp Ala AEIEX4 89 A 0.78 G 0.23 0.35ACCCGGGTACCCACRAGGTGAGGACCCCA AAG GAG Nonsynonymous Lys Glu AEIEX5 197 A0.97 T 0.03 0.06 CTAGAGCTGCGTAGWGTCTTCACCAAGGG AGA AGT Nonsynonymous ArgSer AEIEX8 35 T 0.99 C 0.01 0.03 TTCCCACAGGGAGAYGGGGGCACAGAAGG GAT GACSynonymous Asp Asp AGTEX2 181 C 0.99 T 0.01 0.03AGAGTACCTGTGAGYAGCTGGCAAAGGCC CAG TAG Nonsynonymous Gln STOP AGTEX2 354C 0.99 T 0.01 0.03 GTCGGGATGCTGGCYAACTTCTTGGGCTT GCC GCT Synonymous AlaAla AGTEX2 755 T G GGACTTCACAGAACKGGATGTTGCTGCTG CTG CGG NonsynonymousLeu Arg AGTEX5 258 C 0.96 T 0.04 0.08 TGGCAAGGCCTCTGYCCCTGGCCTTTGAG . .Other 3′UTR AGTEX5 376 C 0.97 G 0.03 0.06 AGCTGGAAAGCAGCSGTTTCTCCTTGGTC. . Other 3′UTR AGTEX5 385 T 0.97 C 0.03 0.06GCAGCCGTTTCTCCYTGGTCTAAGTGTGC . . Other 3′UTR AGTEX5 641 T 0.93 G 0.070.13 GCCTTCGGTTTGTAKTTAGTGTCTTGAAT . . Other 3′UTR AGTEXP1 101 G 0.99 C0.01 0.03 CTGGCTGTGCTATTSTTGGTGTTTAACAG . . Other Promoter AGTEXP2 160 G0.99 A 0.01 0.03 GGAACCTTGGCCCCRACTCCTGCAAACTT . . Other PromoterAGTEXP2 35 G 0.97 A 0.03 0.06 CCCTCTGCACCTCCRGCCTGCATGTCCCT . . OtherPromoter AGTEXP3 158 A 0.71 G 0.29 0.41 CTCGTGACCCGGCCRGGGGAAGAAGCTGC .. Other Promoter AGTEXP3 173 C 0.96 T 0.04 0.08GGGGAAGAAGCTGCYGTTGTTCTGGGTAC . . Other Promoter ALDREDEX1 162 A 0.86 T0.14 0.23 GCGCCAAGATGCCCWTCCTGGGGTTGGGT ATC TTC Nonsynonymous lie PheALDREDEX1 71 C 0.41 G 0.59 0.48 AAAGGTACGCGCCGSGGCCAAGGCCGCAC . . OtherPromoter ALDREDEX10 150 T 0.91 G 0.09 0.16 TTGCAAATGTAGTAKGGCCTGTGTCACTC. . Other 3′UTR ALDREDEX2 180 C 0.94 G 0.06 0.11TGAAGCGTGAGGAGSTCTTCATCGTCAGC CTC GTC Nonsynonymous Leu Val ALDREDEX2204 T 0.95 G 0.05 0.10 TCAGCAAGGTATCGKTCCGCGGTGGGGCT . . Other IntronALDREDEX2 88 A 0.98 T 0.03 0.05 CGTCGGGTACCGCCWCATCGACTGTGCCC CAC CTCNonsynonymous His Leu ALDREDEX3 28 A 0.95 T 0.05 0.10GCCTCTCGCTGGCTTWGCTGTGGTGCACGT . . Other Intron ALDREDEX4 101 G 0.98 A0.03 0.05 AACATTCTGGACACRTGGGCGGTAAGACA ACG ACA Synonymous Thr ThrALDREOEX6 87 G 0.94 A 0.06 0.11 ACTGCCAGTCCAAARGCATCGTGGTGACC GGC AGCNonsynonymous Gly Ser ALDREDEX9 67 C 0.99 T 0.01 0.02CCAGGATATGACCAYCTTACTCAGCTACA ACC ATC Nonsynonymous Thr Ile ANPEX1 252 G0.99 A 0.01 0.03 CCATGTACAATGCCRTGTCCAACGCAGAC GTG ATG Nonsynonymous ValMet ANPEX1 297 C 0.97 T 0.03 0.06 TAGGGCCAGGAAAGYGGGTGCAGTCTGGG . .Other Intron . ANPEX3 106 G 0.97 T 0.03 0.06TCCTGTCCCCTGGGKTCTCTGCTGCATTT . . Other 3′UTR . ANPEX3 127 T 0.91 C 0.090.16 CTGCATTTGTGTCAYCTTGTTGCCATGGA . . Other 3′UTR . APOA1 101 C 0.76 T0.24 0.36 GCCTTGCCCCAGGCYGGGCCTCTGGGTAC . . Other Promoter . APOA1 1016A 0.76 C 0.24 0.36 CGTAACTGGGCACCMGTCCCAGCTCTGTC . . Other Intron .APOA1 1162 G 0.94 C 0.06 0.12 AGGTGTCACCCAGGSCTCACCCCTGATAG . . OtherIntron . APOA1 1163 C 0.93 T 0.08 0.14 GGTGTCACCCAGGGYTCACCCCTGATAGG . .Other Intron . APOA1 1401 G 0.99 C 0.01 0.02TGCAGCCCTACCTGSACGACTTCCAGAAG GAC CAC Nonsynonymous Asp His . APOA1 1576G 0.98 C 0.02 0.04 TGTGGACGCGCTGCSCACGCATCTGGCCC CGC CCC NonsynonymousArg Pro . APOA1 1643 G 0.98 A 0.02 0.04 CTTGAGGCTCTCAARGAGAACGGCGGCGCAAG AAA Synonymous Lys Lys APOAL 1757 C 0.94 G 0.06 0.11CAAGGCCTGCTGCCSGTGCTGGAGAGCTr CCC CCG Synonymous Pro Pro APOAL 2007 T0.64 A 0.36 0.46 CTCCGTGCCCAGACWGGACGTCTTAGGGC . . Other 3′UTR APOA1 334T 0.69 C 0.31 0.43 AACCATCGGGGGGCYTTCTCCCTAAATCC . . Other Intron APOA1620 C 0.92 T 0.08 0.14 TTTGAAGGCTCCGCYTTGGGAAAACAGCT GCC GCT SynonymousAla Ala APOA1 771 C 0.96 T 0.04 0.07 CTGGATGGAGAAACYGGAATGGATCTCCA . .Other Intron APOA1 840 G 0.99 A 0.01 0.02 GGGCTGCCCGATGCRTGATCACAGAGCCA. . Other Intron APOA2 1334 T 0.99 A 0.01 0.03AGATTAGGCTTAAAWTGCAGAGAAAAAGT . . Other Intron APOA2 1412 G 0.82 C 0.180.29 AAGAACTGGGCCTTSAATTTCAGTCTCTA . . Other Intron APOA2 1414 A 0.95 T0.05 0.10 GAACTGGGCCTTGAWTTTCAGTCTCTAGA . . Other intron APOA2 1459 C0.99 T 0.01 0.03 AGCAAAGGTCTTGAYTCTATTCCTACCTA . . Other Intron APOA21672 C 0.94 T 0.06 0.11 AGGCTGGAACGGAAYTGGTTAACTTCTTG CTG TTG SynonymousLeu Leo APOA2 249 T 0.55 C 0.45 0.50 TGCTTCCTGTTGCAYTCAAGTCCAAGGAC . .Other Promoter APOA2 547 A 0.99 C 0.01 0.01GACGCTGGCTAGGTMAGATAAGGAGGCAA . . Other Intron APOA4 1228 A 0.75 G 0.250.38 GACCAGGTGGCCACRGTGATGTGGGACTA ACA ACG Synonymous Thr Thr APOA4 1338T 0.03 C 0.97 0.06 GGGACTACAGTGTGYGGTGGTGACGGGGA . . Other Intron APOA41479 C 0.98 T 0.03 0.05 CCACATATGTAAACYGGAAGTTTGGACCG . . Other IntronAPOA4 1529 T 0.86 C 0.14 0.24 TTGCTTTGACGTTCYAGAGTTTGACAAAT . . OtherIntron APOA4 1597 T 0.59 C 0.41 0.48 GGAGGAAAATGTCAYGTGAGCTGATTTCT . .Other Intron APOA4 1617 G 0.99 A 0.01 0.02 CTGATTTCTAATACRTTTCAGAAAGACAG. . Other Intron APOA4 1879 C 0.94 G 0.06 0.11GATTCTGAGACAAASTATGTGGGAGATCC . . Other Intron APOA4 1961 G 0.96 A 0.040.07 CTGCACCACCATAGRGAGGGTGAACTCGG . . Other Intron APOA4 1998 T 0.63 C0.37 0.47 AGCACTCACCTGTCYTAGCACGTGTGCAT . . Other Intron APOA4 2134 C0.73 T 0.28 0.40 GAAGTGAACACTTAYGCAGGTGACCTGCA TAC TAT Synonymous TyrTyr APOA4 2138 G 0.99 A 0.01 0.02 TGAACACTTACGCARGTGACCTGCAGAAG GGT AGTNonsynonymous Gly Set APOA4 2140 T 0.94 C 0.06 0.12AACACTTACGCAGGYGACCTGCAGAAGAA GGT GGC Synonymous Gly Gly APOA4 2358 A0.89 G 0.11 0.20 GCGCACCCAGGTCARCACGCAGGCCGAGC AAC AGC Nonsynonymous AsnSer APOA4 2698 C 0.95 T 0.05 0.10 ATCTCGGCCAGTGCYGAGGAGCTGCGGCA GCC GCTSynonymous Ala Ala APOA4 2764 C 0.92 T 0.08 0.15CTGAGGGGCAACACYGAGGGGCTGCAGAA ACC ACT Synonymous Thr Thr APOA4 2806 G0.99 A 0.01 0.02 CTGGGTGGGCACCTRGACCAGCAGGTGGA CTG CTA Synonymous LeuLeu APOA4 2837 G 0.98 C 0.02 0.04 AGTTCCGACGCCGGSTGGAGCCCTACGGG GTG CTGNonsynonymous Val Leu APOA4 2926 G 0.81 T 0.19 0.30CATGCGGGGGACGTKGAAGGCCACTTGAG GTG GTT Synonymous VaL VaL APOA4 3058 T0.16 G 0.84 0.26 CAGCAGGAACAGCAKCAGGAGCAGCAGCA CAT CAG Nonsynonymous HisGln APOA4 350 G 0.88 A 0.12 0.21 GCCAGCAGGGCCTCRAGGCATCAGTCCCG . . OtherPromoter APOA4 637 G 0.96 C 0.04 0.08 TGGCGATAGGGAGASAGTTTAAATGTCTG . .Other Promoter APOA4 687 G 0.96 A 0.04 0.07GTTCCCACTGCAGCRCAGGTGAGCTCTCC . . Other Promoter APOC1EX1 1020 G 0.93 T0.07 0.13 TTGTATTTTCAGTAKAGACAGGGTTTCAC . . Other Intron APOC1EX1 1044 G0.95 A 0.05 0.10 TTCACCGTGGTCTCRATCTCCTGACTTTG . . Other Intron APOC1EX11057 T 0.64 C 0.36 0.46 CGATCTCCTGACTTYGTGATCCGCCTGCC . . Other IntronAPOC1EX1 1111 C 0.89 T 0.11 0.20 CAGGCGTGAGCCACYGCGTCCGGCCATTC . . OtherIntron APOC1EX1 1376 G 0.57 T 0.43 0.49 GCACGCGCCTGTAGKCCCAGCTACTCGGG .. Other Intron APOC1EX1 1411 C 0.99 G 0.01 0.02AGGCAGGAGAATCASTTGAACCCGGGAGG . . Other Intron APOC1EX1 432 G 0.97 A0.03 0.06 AGGCTCTTCCTGTCRCTCCCGGTCCTGGT TCG TCA Synonymous Ser SerAPOC1EX1 462 C 0.61 G 0.39 0.47 GTGGTTCTGTCGATSGTCTTGGAAGGTAA ATC ATGNonsynonymous Ile Met APOC1EX1 496 G 0.01 C 0.99 0.02GGATGGGAGAATTGSGGAGTTTGGAGATT . . Other Intron APOC1EX1 713 C 0.99 T0.01 0.02 ACCTCTGGGATTGGYTGTCCTGCTTCGAC . . Other Intron APOC2 1084 T0.91 G 0.09 0.17 TCTGAGGACTCAAGKGCCAAGATGGAGGG . . Other 3′UTR APOC2 126C 0.99 T 0.01 0.02 CAGGTCTCTGGACAYTATGGGCACACGAC . . Other 5′UTR APOC213 T 0.34 A 0.66 0.45 CTGGGACACCGAGCWCACACAGAGCAGGA . . Other PromoterAPOC2 472 G 0.99 A 0.01 0.02 CCCAGAACCTGTACRAGAAGACATACCTG GAG AAGNonsynonymous Glu Lys APOC2 553 G 0.99 A 0.01 0.02TGGCCCATACCACCRACTGCATCCAGGAC . . Other intron APOC2 725 T 0.19 C 0.810.31 CCCAGGAGTCCAGGYCCCCAGACCCTCCT . . Other Intron APOC2 804 A 0.97 T0.03 0.06 TGTGCTTTCTCCCCWGGGACTTGTACAGC . . Other Intron APOC2 819 A0.82 C 0.18 0.30 GGGACTTGTACAGCMAAAGCACAGCAGCC AAA CAA Nonsynonymous LysGln APOC3 1148 T 0.95 A 0.05 0.10 CTGGGGACTAAGAAWGTTTATGAACACCT . .Other Intron APOC3 1322 G 0.71 A 0.29 0.41 CACGGGCTTGAATTRGGTCAGGTGGGGCC. . Other Intron APOC3 1468 A 0.97 C 0.03 0.06ATACGCCTGAGCTCMGCCTCCTGTCAGAT . . Other Intron APOC3 1519 A 0.95 G 0.050.10 GGAGTGTGAACCCTRTTGTGAACTGCACA . . Other Intron APOC3 1637 T 0.96 A0.04 0.07 GGCCCATGGAAAAAWTGTCCACCACAAAA . . Other Intron APOC3 1722 A0.84 G 0.16 0.27 AGGAAAATGGGGCCRGGCGCAGTGGCTCG . . Other Intron APOC31728 A 0.73 G 0.27 0.40 ATGGGGCCAGGCGCRGTGGCTCATGCCTG . . Other IntronAPOC3 736 A 0.85 G 0.15 0.26 AGGCGCAGTGGCTCRTGCCTGTAATCCCA . . OtherIntron APOC3 1774 A 0.76 C 0.24 0.36 GAGGCCGAGGCAGGMGGATCCCCTGAGGT . .Other Intron APOC3 1817 T 0.69 C 0.31 0.43 CAACCTGGCCAACAYGGTGAAACCCCATC. . Other Intron APOC3 1931 C 0.98 T 0.02 0.04TTGAACCCGGGAGAYGGAGGTTGCAGTGA . . Other Intron APOC3 1975 G 0.99 A 0.010.03 CTGCACTCCAGCCTRGGTGACAGAGGGAG . . Other Intron APOC3 2221 G 0.96 A0.04 0.08 AGGGCTAAAACGGCRCGGCCCTAGGACTG . . Other Intron APOC3 2535 G0.81 A 0.19 0.30 GCGTGCTTCATGTARCCCTGCATGAAGCT GGC GGT Synonymous GlyGly APOC3 2854 C 0.70 T 0.30 0.42 CCCTGGGGAGGTGGYGTGGCCCCTAAGGT . .Other Promoter APOC3 429 A 0.69 C 0.31 0.43GCAACCTACAGGGGMAGCCCTGGAGATTG . . Other 3′UTR APOC3 460 G 0.99 C 0.010.03 GGACCCAAGGAGCTSGCAGGATGGATAGG . . Other 3′UTR APOC3 636 G 0.96 A0.04 0.07 TAAATCAGTCAGGGRAAGCAACAGAGCAG . . Other Intron APOC3 954 A0.89 G 0.11 0.19 GTGCAAACAGCACCRCCTGGAGTTGCACA . . Other Intron APOC41150 T 0.39 C 0.61 0.47 AAGTGCTAGGATTAYAGGCGTGAGCCACT . . Other IntronAPOC4 1246 A 0.33 C 0.67 0.44 AGGCTGGTCTTGAAMTCCTGACCTCAGGT . . OtherIntron APOC4 1281 C 0.91 T 0.09 0.16 CCCGCCTTGGCCTCYCAAAGTGCTGGGAT . .Other Intron APOC4 1287 T 0.95 C 0.05 0.10 TTGGCCTCCCAAAGYGCTGGGATTACAGG. . Other Intron APOC4 1313 A 0.42 G 0.58 0.49AGGCATGAGCCACCRCGCCCGGCCATGTA . . Other Intron APOC4 1406 G 0.87 A 0.130.22 ACAGGGCCAGGCACRGTGGCTCATGCCTG . . Other Intron APOC4 1446 G 0.91 A0.09 0.16 CTTTCGGAGGCCGARGCGGGTGGATCGCA . . Other Intron APOC4 1587 C0.29 A 0.71 0.41 CGGGAGGCTGAGGCMGGAGAATCACTTGA . . Other Intron APOC41782 G 0.96 C 0.04 0.07 ATAACCCTGAGGTASATATTATTACCCCG . . Other IntronAPOC4 1794 C 0.94 T 0.06 0.11 TAGATATTATTACCYCGTTCTACAAAAGG . . OtherIntron APOC4 1842 G 0.98 A 0.03 0.05 CAGGATAAGTCACCRGCCAAGGCACACAG . .Other Intron APOC4 1858 T 0.36 C 0.64 0.46 CCAAGGCACACAGCYAGCTACATGTGGCC. . Other Intron APOC4 1875 C 0.96 T 0.04 0.07CTACATGTGGCCCCYGCGTGACGGCTGGT . . Other Intron APOC4 2206 A 0.92 G 0.080.15 TGAAGAGATGGCCCRGCCGGACGGGGTGG . . Other Intron APOC4 2237 C 0.94 T0.06 0.12 CACATCTGTAATCCYAGCATTTTGGGAGC . . Ocher Intron APOC4 2276 T0.65 C 0.35 0.46 TGGATCACTTCAGGYCAGGAGTTCGAGCC . . Other Intron APOC42345 A 0.74 G 0.26 0.38 ATTAGCCGGGCATGRTGGCAGATGCCTGT . . Other IntronAPOC4 2366 T 0.51 A 0.49 0.50 ATGCCTGTAATCCCWGCTACTCGGGAGGC . . OtherIntron APOC4 2767 G 0.99 A 0.01 0.02 AAGATGAGTCGCTGRAGCCTGGTGAGGGG TGGTGA Nonsynonymous Trp Stop APOC4 3027 G 0.98 A 0.03 0.05TCACAGAGAGGAGCRGATAAATGGGGCAG . . Other Intron APOC4 3078 G 0.96 C 0.040.08 GCCTCCACTGTGATSTCCTCTCTCCTGTA . . Other Intron APOC4 3162 T 0.51 G0.49 0.50 GGACCTGGGTCCGCKCACCAAGGCCTGGT CTC CGC Nonsynonymous Leu ArgAPOC4 3252 A 0.91 T 0.09 0.17 TGGGGACAAGGACCWGGGTTAAAATGTTC CAG CTGNonsynonymous Gln Leu APOC4 483 T 0.95 G 0.05 0.10CTGAGAGTGAAGTGKGAATGTCACATTGG . . Other Intron APOC4 931 A 0.97 G 0.030.06 CCAGGCTGGAGTGCRGTGGCGTGATCflG . . Other Intron APOC4 968 C 0.76 T0.24 0.36 CAAGCTCCGCCTCCYGGGTTCACGCCATT . . Other Intron APOER2EX1 454 60.98 C 0.02 0.04 CGCGGCAAGGACTCSGAGGGCTGAGACGC . . Other 5′UTRAPOER2EX12 68 A 0.96 C 0.04 0.07 ACCAACTGTCCAGCMTTGACTTCAGTGGA ATT CTTNonsynonymous Ile Leu APOER2EX13 55 G 0.99 C 0.01 0.02CGAGGCCATTTTCASTGCAAATCGGCTCA AGT ACT Nonsynonymous Ser Thr APOER2EX14162 G 0.98 A 0.03 0.05 GAAGAGGTGCTACCRAGGTAAGCAGACCT CGA CAANonsynonymous Arg Gln APOER2EX17 55 A 0.98 G 0.03 0.05TACCTGATCTGGAGRAACTGGAAGCGGAA AGA AGG Synonymous Arg Arg APOER2EX19 1005G 0.52 C 0.48 0.50 CAGAGTGCTCAGAAASTCAAGATAGGATAT . . Other 3′UTRAPOER2EX19 1060 T 0.96 C 0.04 0.07 TAAAGTTCAGCTCTYTGAGTAACTTCTTC . .Other 3′UTR APOER2EX19 1149 A 0.98 T 0.03 0.05TGCCATCCTTACAGWGCTAAGTGGAGACG . . Other 3′UTR APOER2EX19 13 G 0.51 A0.49 0.50 GTTGTCTCCCCAGCRAGTGGCATTAAGCC CGA CAA Nonsynonymous Arg GlnAPOER2EX19 602 A 0.93 G 0.07 0.13 TTTAGAGAAGTGAGRGTATTTATTTTTGG . .Other 3′UTR APOER2EX19 931 A 0.99 C 0.01 0.02CCATGGCTGCTGTGMCTCCTACCAGGGCT . . Other 3′UTR APOER2EX9 116 G 0.99 A0.01 0.03 TGCTCAAGAATGTCRTGGCACTAGATGTG GTG ATG Nonsynonymous Val MetAPOER2EX9 157 G 0.99 C 0.01 0.02 AATCGCATCTACTGSTGTGACCTCTCCTA TGG TGCNonsynonymous Trp Cys AT1EX5 1158 A 0.95 G 0.05 0.10TGAGGTTGAGTGACRTGTTCGAAACCTGT . . Other 3′UTR AT1EX5 1226 T 0.92 G 0.080.15 TCCTCTGCAGCACTKCACTACCAAATGAG . . Other 3UTR AT1EX5 1242 A 0.53 C0.47 0.50 ACTACCAAATGAGCMTTAGCTACTTTTCA . . Other 3′UTR AT1EX5 1249 A0.99 G 0.01 0.03 AATGAGCATTAGCTRCTTTTCAGAATTGA . . Other 3′UTR ATIEX51473 G 0.91 A 0.09 0.17 CCTGCTTTTGTCCTRTTATTTTTTATTTC . . AT2EX3 1355 T0.39 G 0.61 0.47 GTTTGTACAAGATTKTCATTGGTGAGACA . . Other 3′UTR AT2EX31361 G 0.69 A 0.31 0.43 ACAAGATTTTCATTRGTGAGACATATTTA . . Other 3′UTRAT2EX3 562 T 0.99 C 0.01 0.03 TATATAGTTCCCCTYGTTTGGTGTATGGC CTT CTCSynonymous Leu Leu AT2EX3 807 G 0.94 A 0.06 0.12CTATGGGAAGAACARGATAACCCGTGACC AGG AAG Nonsynonymous Arg Lys AT2EX3 844 T0.93 C 0.07 0.13 AAGATGGCAGCTGCYGTTGTTCTGGCCTT GCT GCC Synonymous AlaAla AVPEX2 154 C 0.96 T 0.04 0.08 GGAGAACTACCTGCYGTCGCCCTGCCAGT CCG CTGNonsynonymous Pro Leu AVPR2EX1 114 A 0.97 T 0.03 0.06TCATGGCGTCCACCWCTTCCGGTAAGGCT ACT TCT Nonsynonymous Thr Ser AVPR2EX2 109G 0.98 A 0.02 0.04 ACCCGGGACCCGCTRCTAGCCCGGGCGGA CTG CTA Synonymous LeuLeu AVPR2EX2 129 C 0.85 T 0.15 0.25 CCGGGCGGAGCTGGYGCTGCTCTCCATAG GCGGTG Nonsynonymous Ala Val AVPR2EX2 184 G 0.94 T 0.06 0.11GGCCTGGTGCTGGCKGCCCTAGCTCGGCG GCG GCT Synonymous Ala Ala AVPR2EX2 444 C0.87 T 0.13 0.23 CCGTCCCATGCTGGYGTACCGCCATGGAA GCG GTG Nonsynonymous AlaVal AVPR2EX3 112 C 0.95 T 0.05 0.10 TCTTTCAGCAGCAGYGTGTCCTCAGAGCT AGCAGT Synonymous Ser Ser AVPRIEX3 232 G 0.95 A 0.05 0.10AAGGACACTTCATCRTGAGGAGCTGTTGG TCG TCA Synonymous Ser Ser AVPR2EX3 252 T0.97 C 0.03 0.06 AGCTGTTGGGTUTCYTGCCTCTAGAGGCT . . Other 3′UTR .AVPR2EX3 46 A 0.50 G 0.50 0.50 GCCCCCTTTGTGCTRCTCATGTTGCTGGC CTA CTGSynonymous Leu Leu BIR 1069 C 0.98 T 0.03 0.05CAGGACTGGCTGGAYCCACAGCTCTAGGG . . Other 3′UTR . BIR 1142 G 0.67 A 0.330.44 GGTGAGCCAGTCCTRAATTGGGTTGGGAG . . Other 3′UTR . BIR 1185 G 0.98 T0.03 0.05 ATAACCCAGTACAGKTTCCTGCTGAGGCC . . Other 3′UTR . BIR 1265 G0.95 A 0.05 0.10 GGAGGCTGAGCTGARGCTCGCCCAGCCTC . . Other 3′UTR . BIR1295 C 0.24 7 0.76 0.37 CACCAGGCCCTGGCYGGGCTACATACCAC . . Other 3′UTR .BIR 1441 T 0.99 C 0.01 0.02 AGGGGCCCGCGGGCYGAGGCGAGGGTCAG TCA TCGSynonymous Ser Ser BIR 1521 C 0.26 T 0.74 0.38TGTGGGCACTTTGAYGGTGTTGCCAAACT GTC ATC Nonsynonymous Val Ile BIR 1729 G0.99 C 0.99 0.03 GGTGCCAGGTCGTASAGTGGGCTGTTGGC CTC CTG Synonymous LeuLeu BIR 1946 C 0.99 T 0.01 0.02 GCATGAAGCAGAGGYGGCCGTGGCGCAGG CCC CACNonsynonymous Arg His BIR 1960 G 0.75 A 0.25 0.38CGGCCGTCGCGCAGRGCGATCACCGCATG CCC GCT Synonymous Ala Ala BIR 2463 T 0.22C 0.78 0.34 ACGGTACCTGGGCTYGGCAGGGTCCTCTG AAG GAG Nonsynonymous Lys GluBIR 2664 T 0.97 C 0.03 0.06 TGTGCTGGCCTCACVTCTGAGATAACTCC . . Other5′UTR BIR 2894 T 0.99 G 0.01 0.03 TGGTGGTGCGCACCKGTAATCCCACCTAC . .Other Promoter BIR 2954 G 0.97 C 0.03 0.06 CCCGAGAGGCGGAGSTTGCAGTGAGCCAA. . Other Promoter BIR 3174 C 0.70 T 0.30 0.42TCCCGCTAAGAGCCYTTCTCCCCGCCCAG . . Other Promoter BIR 369 G 0.97 A 0.030.06 CAACACTGCTCCAARGGTCCAGGCACGGG . . Other 3′UTR . BIR 510 T 0.99 C0.01 0.02 CCTTCTGGACAAAGYGAGTGGCAGCCACT . . Other 3′UTR . BIR 657 T 0.92A 0.08 0.14 CACAGAGCCCTCACWGCACGAGGCCGATG . . Other 3′UTR . BIR 981 G0.98 A 0.03 0.05 TTGGAGCCACAGACRCAAAGCAGCAGCCC . . Other 3′UTR .BKRB2EX1 55 T 0.77 G 0.23 0.35 GGTGGGGACGGTGGKGACGGTGGGGACAT . . Other5′UTR . BKRB2EX3 1513 T 0.93 C 0.07 0.13 ATCTCCAGGAGAACYGCCATCCAGCTTTG .. Other 3′UTR . BKRB2EX3 1833 G 0.95 A 0.05 0.10ACTCAAGTGGGAACRACTGGGCACTGCCA . . Other 3′UTR . BKRB2EX3 747 0.093 A0.07 0.13 AAGGAGATCCAGACRGAGAGGAGGGCCAC ACG ACA Synonymous Thr ThrBNPEX1 343 G 0.99 T 0.01 0.02 TTTCCTGGGAGGTCKTTCCCACCCGCTGG CGT CTTNonsynonymous Arg Leu BNPEX2 15 C 0.97 G 0.03 0.07TGAGGCTTGGACGCSCCCATTCATTGCAG . . Other Intron . BNPEX2 174 A 0.99 T0.01 0.02 GTGGGCACCGCAAAWTGGTCCTCTACACC ATG TTG Nonsynonymous Met LeuBNPEX2 37 G 0.97 A 0.03 0.06 ATTGCAGGAGCAGCRCAACCATTTGCAGG CGC GAGNonsynonymous Arg His BRS3EX1 424 G 0.95 A 0.05 0.10AGAACTGAAGCAAARGAGTATCTGGATGT . . Other Promoter BRS3EX1 730 A 0.97 C0.03 0.06 GTGCCATCTATATTMCTTATGCTGTGATC ACT CCT Nonsynonymous Thr ProBRS3EX1 879 A 0.95 T 0.05 0.10 CTAACTTGTGTGCCWGTGGATGCAACTCA CCA CCTSynonymous Pro Pro BRS3EX2 144 T 0.94 A 0.06 0.11GCTCTACCTGAGGCWATATTTTCAAATGT GCT GCA Synonymous Ala Ala BRS3EX2 80 T0.98 A 0.02 0.04 CTCCAATGCCATCCWGAAGACTTGTGTAA CTG GAG Nonsynonymous LeuGln BRS3EX3 173 T 0.94 C 0.06 0.12 GCCATGCATTTCATYTTCACCATTTTCTC ATT ATCSynonymous Ile Ile Other 5′UTR CAL/CGRPEX1+2 1063 T 0.98 G 0.02 0.05CCCCAGTCACAGGCKCTGGGAGCAAAGAG . . Other 5═UTR . CAL/CGRPEX1+2 940 G 0.86A 0.14 0.24 GTGCGATCAGGGACRGCGTCTGGAGCCCA . . Other 5′UTR . CAL/CGRPEX3112 G 0.92 A 0.08 0.15 CTGCACTGGTGCAGRACTATGTGCAGATG GAC AACNonsynonymous Asp Asn CAL/CGRPEX3 120 G 0.99 T 0.01 0.02GTGCAGGACTATGTKCAGATGAAGGCCAG GTG GTT Synonymous Val Val CAL/CGRPEX4 30C 0.91 A 0.09 0.16 TGTTTTCCCTGCAGMCTGGACAGCCCCAG AGC AGA NonsynonymousSer Arg CAL/CGRPEX5 309 A 0.59 T 0.41 0.48 ATGTGGTTTTAAAAWATCCATAAGGGAAG. . Other 3′UTR . CAL/CGRPEX5 433 C 0.78 T 0.22 0.34CAGACCAAGAAATAYAGATCCTGTTTATT . . Other 3′UTR . CAL/CGRPEX5 719 G 0.91 A0.09 0.16 AAAGAGCAAGTGAGRTAATAGATGTTAAG . . Other 3′UTR . CHYEX1 158 T0.86 A 0.14 0.24 TTGCCTTCTGGGAGWTATAAAACCCAAGA . . Other 5′UTR . CHYEX165 T 0.70 C 0.30 0.42 TCTAGGGGAACTTCYGATCAGAAACAGCC . . Other 5′UTR .CHYEX2 107 G 0.95 C 0.05 0.09 TTGTAACTTCCAACSGTCCCTCAAAATTT GGT CGTNonsynonymous Gly Arg CHYEX2 168 A 0.92 G 0.08 0.14GCTGACGGCTGCTCRTTGTGCAGGAAGGT CAT CGT Nonsynonymous His Arg CHYEX3 26 A0.91 G 0.09 0.17 CCTTCTTCCTCACARCAGGTCTATAACAG . . Other Intron . CHYEX483 A 0.92 C 0.08 0.15 CTCCCCTTCCCATCMCAATTCAACflTGT TCA TCC SynonymousSer Ser CHYEX5 274 C 0.89 T 0.11 0.19 TCCCTCAGCCACAAYCCTAAGCCTCCAGA . .Other 3′UTR CLCNKBEX10 33 G 0.56 C 0.44 0.49CTCTGGCCACCTTGSTTCTCGCCTCCATC GTT CTT Nonsynonymous Val Leu CLCNKBEX1312 C 0.94 T 0.06 0.12 GGAGGAGCTGCTATYGGGCGCCTCTTTGG ATC ATT SynonymousIle Ile CLCNKBEX15 64 C 0.94 T 0.06 0.11 ACTGGCCAAGGACAYGCCACTGGAGGAGGACG ATG Nonsynonymous Thr Met CLCNKBEX15 68 A 0.34 G 0.66 0.45GCCAAGGACACGCCRCTGGAGGAGGTGGT CCA CCG Synonymous Pro Pro CLCNKBEX18 51 C0.96 T 0.04 0.08 CCTCTTTGTGACGTYGCGGGGCAGAGCTG TCG TGG Nonsynonymous SerTrp CLCNKBEX3 34 A 0.94 C 0.06 0.11 GGGAGATTGGGGACMGCCACCTGCTCCGG AGCCGC Nonsynonymous Ser Arg CLCNKBEX3 96 G 0.93 A 0.07 0.13GTCTCTTTCTCTTCRGGCTTCTCTCAGAG TCG TCA Synonymous Ser Ser CLCNKBEX4 19 G0.35 C 0.65 0.46 TGGAATCCCGGAGSTGAAGACCATGTTG GTG GTG Nonsynonymous ValLeu CLCNKBEX4 70 A 0.92 C 0.08 0.15 ACCTGGATATCAAGMACTTTGGGGCCAAA AACCAC Nonsynonymous Asn His CLCNKBEX7 108 G 0.89 A 0.11 0.20TTCCGGCTCCTGGCRGTCTTCAACAGCGA GCG GCA Synonymous Ala Ala CNPEX1 1018 C0.91 A 0.09 0.16 GCAGCGCCAACTTTMTGCCTGTATGACTT . . Other 5′UTR . CNPEX1144 G 0.98 T 0.02 0.04 GCCTTCACGCCTGGKGACAGCCACTGCAC . . Other 5′UTR .CNPEX1 1457 C 0.98 G 0.02 0.05 GCAGCACTGGGACCSTGCTCGCCCTGCAG . . Other5′UTR . CNPEX1 578 G 0.91 A 0.09 0.16 ATTGTTCCCACAGARGGAGTTCACCAGCG . .Other 5′UTR . CNPEX1 592 G 0.94 A 0.06 0.11GGGAGTTCACCAGCRGAGTCAGACCCCGG . . Other 5′UTR . CNPEX2 1171 T 0.92 A0.08 0.14 AACATCCCAGCCTCWGACATTGACAGTCA . . Other 3′UTR . CNPEX2 139 G0.96 A 0.04 0.08 GGACACCAAGTCGCRGGCAGCGTGGGCTC CGG CAG Nonsynonymous ArgGln CNPEX2 357 A 0.95 G 0.05 0.10 GCCCGCCGCCCAGCCRGCCTTCGGAGGCGC . .Other 3′UTR . CNPEX2 41 T 0.98 C 0.02 0.03 GCTGCGGGCGGCGGYCAGAAGAAGGGCGAGGT GGC Synonymous Gly Gly COX1 1063 A 0.99 G 0.01 0.02TTTCCTGCAGCTGARATTTGACCCAGAGC AAA AGA Nonsynonymous Lys Arg COX1 1314 A0.99 G 0.01 0.02 ACATGGACCACCACRTCCTGCATGTGGCT ATC GTC Nonsynonymous IleVal COX1 1386 A 0.99 G 0.01 0.02 TCAATGAGTACCGCRAGAGGTTTGGCATG AAG GAGNonsynonymous Lys Glu COX1 1428 G 0.98 A 0.02 0.03CCTTCCAGGAGCTCRTAGGAGAGAAGGAG GTA ATA Nonsynonymous Val Ile COX1 1906 T0.96 C 0.04 0.08 GGTGAGTGTTGGGGYTGACATTTAGAACT . . Other 3′UTR . COX11948 T 0.99 C 0.01 0.02 ATTATCTGGAATATYGTGATTCTGTTTAT . . Other 3′UTR .COX1 2037 T 0.99 G 0.01 0.02 GTCTGCCAGAATACKGGGTTCTTAGTTGA . . Other3′UTR . COX1 310 G 0.99 A 0.01 0.02 TGCCACCTTCATCCRAGAGATGCTCATGC CGACAA Nonsynonymous Arg Gln COX1 626 C 0.91 A 0.09 0.16TTCAAAACTTCTGGMAAGATGGGTCCTGG GGC GGA Synonymous Gly Gly COX1 696 C 0.98A 0.02 0.03 TTTATGGAGACAATMTGGAGCGTCAGTAT CTG ATG Nonsynonymous Leu MetCOX1 938 T 0.98 C 0.02 0.04 GACCTGCTGAAGGCYGAGCACCCCACCTG GCT GCCSynonymous Ala Ala COX2EX1 186 C 0.84 G 0.16 0.27CGATTTTCTCATTTSCGTGGGTAAAAAAC . . Other Promoter . COX2EX1 358 T 0.84 G0.16 0.27 GCGACCAATTGTCAKACGACTTGCAGTGA . . Other Promoter COX2EX10 156T 0.94 C 0.06 0.12 AACCATGGTAGAAGYTGGAGCACCATTCT GTT GCT NonsynonymousVal Ala COX2EX10 379 C 0.98 A 0.03 0.05 GCAAGTTCTTCCCGMTCCGGACTAGATGACGC CGA Synonymous Arg Arg COX2EX10 866 T 0.51 C 0.49 0.50AAAGTACTTTTGGTYATTTTTCTGTCATC . . Other 3′UTR . COX2EX10 87 A 0.99 G0.01 0.02 CATCGATGCTGTGGRGCTGTATCCTGCCC GAG GGG Nonsynonymous Glu GlyCOX2EX10 937 G 083 A 0.17 0.28 ATTAGACATTACCARTAATTTCATGTCTA . . Other3′UTR . COX2EX3 166 G 0.93 C 0.07 0.13 ATTATGAGTTATGTSTTGACATGTAAGTA GTGGTC Synonymous Val Val COX2EX7 206 T 096 C 0.04 0.07AACAGAGTATGCGAYGTGCTTAAACAGGA GAT GAC Synonymous Asp Asp COX2EX8 268 T0.95 C 0.05 0.10 ATATTGCTGGAACAYGGAATTACCCAGTT CAT CAC Synonymous HisHis CYPIIB1EX1 351 T 0.97 C 0.03 0.06 TGACGTGATCCCTCYCGAAGGCAAGGCAC . .Other Promoter . CYPIIB1EX1 525 C 0.99 G 0.01 0.03AGGACAGTGCTGCCSTTTGAAGCCATGCC CCC CCG Synonymous Pro Pro CYPIIB1EX1 542G 0.97 A 0.03 0.06 TGAAGCCATGCCCCRGCGTCCAGGCAACA CGG CAG NonsynonymousArg Gln CYPIIB1EX1 601 G 0.97 C 0.03 0.06 AGCAGGGTTATGAGSACCTGCACCTGGAAGAC CAC Nonsynonymous Asp His CYPIIB1EX2 184 C 0.99 T 0.01 0.03GTGGCGTGTTCTTGYTGTAAGCGGCGAGC CTG TTG Synonymous Leu Leu CYPIIB1EX2 188A 0.96 G 0.04 0.07 CGTGTTCTTGCTGTRAGCGGCGAGCTGAG . . Other Intron .CYPIIB1EX2 36 T 0.46 C 0.54 0.50 CCCCACAGGTACGAYTTGGGAGGAGCAGG GAT GACSynonymous Asp Asp CYPIIB1EX2 78 C 0.96 T 0.04 0.08ATGCTGCCGGAGGAYGTGGAGAAGCTGCA GAC GAT Synonymous Asp Asp CYPIIB1EX3 114G 0.99 C 0.01 0.02 AGGTTCCTCCCGATSGTGGATGCAGTGGC ATG ATC NonsynonymousMet Ile CYPIIB1EX4 177 C 0.98 T 0.02 0.04 CCTGTCTCGCTGGAYCAGCCCCAAGGTGTACC ATC Nonsynonymous Thr Ile CYPIIB1EX4 205 T 0.92 G 0.08 0.15TGGAAGGAGCACTTKGAGGCCTGGGACTG TTT TTG Nonsynonymous Phe Leu CYPIIB1EX4247 C 0.91 G 0.09 0.16 GGTGAGGCCAGGGASCCGGGCAGTGCTAT . . CYPIIB1EX5 103G 0.97 A 0.03 0.06 ACCAGCATCGTGGCRGAGCTCCTGTTGAA GCG GCA Synonymous AlaAla CYPIIB1EX5 107 C 0.84 G 0.16 0.26 GCATCGTGGCGGAGSTCCTGTTGAATGCG CTCGTC Nonsynonymous Leu Val CYPIIB1EX5 16 C 0.58 T 0.42 0.49TGAGGGCTGCCTCCYGCTCCCCGGATAGG . . Other Intron . CYPIIB1EX5 55 T 0.97 C0.03 0.06 ATCCAGAAAATCTAYCAGGAACTGGCCTT TAT TAC Synonymous Tyr TyrCYPIIB1EX5 72 G 0.99 A 0.01 0.03 GGAACTGGCCTTCARCCGCCCTCAACAGT AGC AACNonsynonymous Ser Asn CYPIIB1EX7 52 C 0.99 T 0.01 0.03CTGTGGGTCTGTTTYTGGAGCGAGTGGCG CTG TTG Synonymous Leu Leu CYPIIBlEX8 144T 0.96 C 0.04 0.08 CCGGCAGGAACTTCYACCACGTGCCCTTT TAC CAC NonsynonymousTyr His CYPIIB1EX9 16 G 0.96 C 0.04 0.07 CCAGATGGAAACCCSGCTTCTGTCCTAGG .. Other Intron . CYPIIB1EX9 274 T 0.91 C 0.09 0.16AGCCCCAGCACAAAYGGAACTCCCGAGGG . . Other 3′UTR . CYPIIB1EX9 350 T 0.88 G0.12 0.21 GCTGGGGAAGATCTKGCTGACCTTGTCCC . . Other 3′UTR . CYPIIB1EX9 459G 0.72 A 0.28 0.40 CCTCGTGTGGCCATRCAAGGGTGCTGTGG . Other 3′UTR .CYPIIB1EX9 592 A 0.93 C 0.07 0.13 TCTAGAGTCCAGTCMAGTTCCCTCCTGCA . .Other 3′UTR . CYPIIBiEX9 62 C 0.99 7 0.01 0.03GTGGAGACACTAACYCAAGAGGACATAAA ACC ACT Synonymous Thr Thr CYPIIB1EX9 657G 0.66 A 0.34 0.45 CTCTGAAAGTTGTCRCCCTGGAATAGGGT . . Other 3′UTR .CYPIIB1EX9 786 A 0.87 G 0.13 0.22 ATCGTGTCAGCCTCRTGCCCCTGGCCTCA . .Other 3′UTR . CYPIIB1EX9 835 C 0.77 T 0.23 0.35GTTCCAGGAGTGGGYGTTGGGTCCTCTGC . . Other 3′UTR . CYPIIB1EX9 879 A 0.68 G0.32 0.44 CTGGGGAAGGTCCCRAGGATGCTGTCAGG . . Other 3′UTR . CYPIIB2EX1 163A 0.97 G 0.03 0.06 TCCTGGGTGAGATARAAGGATTTGGGCTG . . Other Promoter .CYPIIB2EX3 138 C 0.66 T 0.34 0.45 GTGGCCAGGGACTTYTCCCAGGCCCTGAA TTC TTTSynonymous Phe Phe CYPIIB2EX3 152 A 0.71 G 0.29 0.41CTCCCAGGCCCTGARGAAGAAGGTTGCTGC AAG AGG Nonsynonymous Lys Arg CYPIIB2EX320 G 0.98 C 0.03 0.05 CAAGCTCTGCCCTGSCCTCTGTAGGAATG . . Other Intron .CYPIII32EX3 243 G 0.97 A 0.03 0.06 GGTGTGGGCCATGCRGGAAGGTCCAGCCC . .Other Intron . CYPIIB2EX4 177 T 0.96 C 0.04 0.07CCTGTCTCGCTGGAYCAGCCCCAAGGTGT ATC ACC Nonsynonymous Ile Thr CYPIIB2EX4250 G 0.98 A 0.02 0.04 GAGGCCAGGGACCCRGGCAGTGCTATGGG . . Other Intron .CYPIIB2EX4 99 A 0.94 C 0.06 012 TTCTGCCAGCCTGAMCTTCCTCCATGCCC AAC ACCNonsynonymous Asn Thr CYPIIB2EX5 103 G 0.05 A 0.95 0.10ACAGGCATCGTGGCRGAGCTCCTGTTGAA GCG GCA Synonymous Ala Ala CYPIIB2EX5 121G 0.78 A 0.23 0.35 CTCCTGTTGAAGGCRGAACTGTCACTAGA GCG GCA Synonymous AlaAla CYPIIB2EX5 55 C 0.99 T 0.01 0.02 ATCCAGAAAATCTAYCAGGAACTGGCCTT TAGTAT Synonymous Tyr Tyr CYPIIB2EX5 72 A 0.99 G 0.01 0.02GGAACTGGCCTTCARCCGCCCTCAACACT AAC AGC Nonsynonymous Asn Ser CYPIIB2EX6195 A 0.84 C 0.16 0.27 TCAAGGAGACCTTGMGGTGGGTGCTGGCT AGG CGG SynonymousArg Arg CYPIIB2EX6 91 T 0.38 C 0.63 0.47 CGACGTGCAGCAGAYCCTGCGCCAGGAGAATC ACC Nonsynonymous Ile Thr CYPIIB2EX7 52 T 0.99 C 0.01 0.03CTGTGGGTCTGTTTYTGGAGCGAGTGGTG TTG CTG Synonymous Leu Leu CYPIIB2EX7 56 A0.97 T 0.03 0.06 GGGTCTGTTTTTGGWGCGAGTGGTGAGCT GAG GTG Nonsynonymous GluVal CYPIIB2EX7 65 T 0.91 C 0.09 0.17 TTTGGAGCGAGTGGYGAGCTCAGACTTGG GTGGCG Nonsynonymous Val Ala CYPIIB2EX7 78 G 0.82 A 0.18 0.30GTGAGCTCAGACTTRGTGCTTCAGAACTA TTG TTA Synonymous Leu Leu CYPIIB2EX8 132G 0.97 A 0.03 0.06 ACATCAGGGGCTCCRGCAGGAACTTCCAC GGC AGC NonsynonymousGly Ser CYPIIB2EX8 18 C 0.99 T 0.01 0.02 TGATCCCTGCTCTGYACCGTCCGCAGACA .. Other Intron . CYPIIB2EX8 182 C 0.98 T 0.02 0.04ATGCGCCAGTGCCTYGGGCGGCGCCTGGC CTC CTT Synonymous Leu Leu CYPIIB2EX8 37 T0.99 A 0.01 0.02 TCCGCAGACATTGGWACAGGTTTTCCTCT GTA GAA Nonsynonymous ValGlu CYPIIB2EX9 224 G 0.89 A 0.11 0.20 GTCTTCTCTCCCACRTGCACAGCTTCCTG . .Other 3′UTR . CYPIIB2EX9 90 T 0.99 G 0.01 0.03AGATGGTCTACAGCKTCATATTGAGGCCT TTC GTC Nonsynonymous Phe Val DBHEX1 152 G0.99 A 0.01 0.02 GGGCCAGCCTGCCCRGCCCCAGCATGCGG . . Other 5′UTR . DBHEX3153 G 0.92 A 0.08 0.14 AGTTGCCCTCAGACRCGTGCACCATGGAG GCG ACGNonsynonymous Ala Thr DBHEX3 239 G 0.97 C 0.03 0.06AAGGAGCTTCCAAASGGCTTCTCTCGGCA AAG AAC Nonsynonymous Lys. Asn DBHEX3 257C 0.98 T 0.03 0.05 TTCTCTCGGCACCAYATTATCAAGGTACG CAC CAT Synonymous HisHis DBHEX3 63 G 0.96 C 0.04 0.08 CGTTCCGGTCACTGSAGGCCATCAACGGC GAG CAGNonsynonymous Glu Gly DBHEX4 12 G 0.96 C 0.04 0.08CCTCCTCACAGTACSAGCCCATCGTCACC GAG CAG Nonsynonymous Glu Gln DBHEX4 132 G0.94 A 0.06 0.11 CCAAGATGAAACCCRACCGCCTCAACTAC GAC AAC Nonsynonymous AspAsn DBHEX5 37 T 0.94 C 0.06 0.11 AGAGGAAGCCGGCCYTGCCTTCGGGGGTC CTT CCTNonsynonymous Leu Pro DBHEX5 39 G 0.94 T 0.06 0.11AGGAAGCCGGCCTTKCCTTCGGGGGTCCA GCC TCC Nonsynonymous Ala Ser DDIR 122 A0.84 G 0.16 0.27 CCTATTCCCTGCTTRGGAACTTGAGGGGT . . Other Promoter . DDIR1521 G 0.96 A 0.04 0.08 CTGAACTCGCAGATRAATCCTGCCACACA . . Other 3′UTR .DDIR 278 A 0.96 C 0.04 0.08 TGCTCATCCTGTCCMCGCTCCTGGGGAAC ACG CCGNonsynonymous Thr Pro DDIR 279 C 0.99 G 0.01 0.02GCTCATCCTGTCCASGCTCCTGGGGAACA ACG AGG Nonsynonymous Thr Arg DDIR 310 C0.98 G 0.02 0.04 CTGGTCTGTGCTGCSGTTATCAGGTTCCG GCC GCG Synonymous AlaAla DDIR 319 G 0.99 T 0.01 0.02 GCTGCCGTTATCAGKTTCCGACACCTGCG AGG AGTNonsynonymous Arg Ser DDIR 76 G 0.98 A 0.03 0.05GCAAAGTGCTGCCTRGTGGGGAGGACTCC . . Other Promoter . DDIR 764 T 0.98 G0.03 0.05 ATGCCATCTCATCCKCTGTAATAAGCTTT TCT GCT Nonsynonymous Ser AlaEDNRAEX6 124 A 0.28 G 0.72 0.40 ACTGTGTATAACGARATGGACAAGAACCG GAA GAGSynonymous Glu Glu EDNRAEX6 88 C 0.31 T 0.69 0.43TGGTTCCCTCTTCAYTTAAGCCGTATATT CAC CAT Synonymous His His EDNRAEX8 1157 G0.66 A 0.34 0.45 TTTTCAGATGATTCRGAAATTTTCATTCA . . Other 3′UTR .EDNRAEX8 1380 C 0.52 T 0.48 0.50 ACGATTCTTCACTTYTTGGGGTTTTCAGT . . Other3′UTR . EDNRAEX8 1687 A 0.83 G 0.17 0.28 TTGTGCCAAAGTGCRTAGTCTGAGCTAAA .. Other 3′UTR . EDNRAEX8 228 C 0.47 G 0.53 0.50CAAGGCAACTGTGASTCCGGGAATCTCTT . . Other 3′UTR . EDNRAEX8 295 A 0.99 G0.0 0.02 AAGAAATGCTTTCCRAAACCGCAAGGTAG . . Other 3′UTR . EDNRAEX8 622 G0.38 A 0.62 0.47 ACAATATGGGCTCARGTCACTTTTATTTG . . Other 3′UTR .EDNRAEX8 655 G 0.99 A 0.01 0.03 GTCATTTGGTGCCARTATTTTTTAACTGC . . Other3′UTR . EDNRAEX8 788 A 0.88 G 0.12 0.21 CTATTTATTTTTTTRAAACACAAATTCTA .. Other 3′UTR . EDNRAEX8 950 T 0.96 C 0.04 0.08GAACATGTTTTGTAYGTTAAAFICAAAAG . . Other 3′UTR . EDNRAEX8 985 T 0.97 C0.03 0.06 TTCAATCAGATAGTYCTTTTTCACAAGTT . . Other 3′UTR . EDNRBEX1 33 T0.98 A 0.03 0.05 GCCGCCTCCAAGTCWGTGCGGACGCGCCC CTG CAG Nonsynonymous LeuGln EDNRBEX1 347 T 0.99 G 0.01 0.02 TGTCCTGCCTTGTGKTCGTGCTGGGGATC TTCGTC Nonsynonymous Phe Val EDNRBEX1 62 C 0.99 T 0.01 0.02TGGTTGCGCTGGTTYTTGCCTGCGGCCTG CTT TTT Nonsynonymous Leu Phe EDNRBEX2 78C 0.95 T 0.05 0.10 ATACAGAAAGCCTCY0T000AATCACT0T TCC TCT Synonymous SerSer EDNRBEX2 87 C 0.99 T 0.01 0.03 GCCTCCGTGGGAATYACTGTGCTGAGTCT ATC ATTSynonymous Ile Ile EDNRBEX3 144 C 0.94 T 0.06 0.11TTTTGATATAATTAYGATGGACTACAAAG ACG ATG Nonsynonymous Thr Met EDNRBEX4 122G 0.99 A 0.01 0.03 GTTGAGAAAGAAAARTGGCATGCAGATTG AGT AAT NonsynonymousSer Asn EDNRBEX4 39 G 0.82 A 0.18 0.29 AAAGATTGGTGGCTRTTCAGTTTCTAflT CTGCTA Synonymous Leu Leu ELAMIEX1 143 A 0.93 G 0.07 0.13TCTTTGACCTAAATRATGAAAGTCTTAAA . . Other Promoter . ELAMIEX1 209 T 0.97 G0.03 0.06 TTATTGCACTAGTOKCCTTTGCCCAAAAT . . Other Promoter . ELAMIEX10107 C 0.91 T 0.09 0.16 CATTAGCACCATTTYTCCTCTGGCTTCGG CTC TTCNonsynonymous Leu Phe ELAMIEX12 54 T 0.96 C 0.04 0.08AGCCTTGAATCAGAYGGAAGCTACCAAAA GAT GAG Synonymous Asp Asp ELAMIEX13 1004T 0.98 G 0.02 0.04 CAGAAATATGTGGTKTCCACGATGAAAAA . . Other 3′UTR .ELAMIEX13 1158 6 0.18 A 0.82 0.29 GATGTTTGTCAGATRTGATATGTAAACAT . .Other 3′UTR . ELAM1EX13 1549 G 0.39 A 0.61 0.47TGAACACTGGCAACRACAAAGCCAACAGT . . Other 3′UTR . ELAM1EX13 967 T 0.97 C0.03 0.06 ACTGAATGGAAGGTYTGTATATTGTCAGA . . Other 3′UTR . ELAM1EX2 382 C0.98 G 0.02 0.04 AATGATGAGAGGTOSAGCAAGAAGAAGCT TGC TGG Nonsynonymous CysTrp ELAMIEX3 152 T 0.95 C 0.05 0.10 GTAAGTCTGGTTCTYGCCTCTTTCTTCAC . .Other Intron . ELAMIEX3 53 A 0.97 C 0.03 0.06CCAATACATCCTGCMGTGGCCACGGTGAA AGT CGT Nonsynonymous Ser Arg ELAMIEX5 197G 0.95 A 0.05 0.10 GGAATTGGGACAACRAGAAGCCAACGTGT GAG AAG NonsynonymousGlu Lys ELAMIEX5 55 T 0.97 C 0.03 0.06 GATGCTGTGACAAAYCCAGCCAATGGGTT AATAAC Synonymous Asn Asn ELAMIEX7 199 C 0.94 T 0.06 0.12GGGGAGTGGGACAAYGAGAAGCCCACATG AAC AAT Synonymous Asn Asn ELAM1EX7 200 G0.94 C 0.06 0.11 GGGAGTGGGACAACSAGAAGCCCACATGT GAG CAG Nonsynonymous GlnGln ELAM1EX8 152 C 0.96 T 0.04 0.08 AGGGATTTGAATTAYATGGATCAACTCAA CATTAT Nonsynonymous His Tyr ELAMIEX8 22 T 0.91 C 0.09 0.16AGTGCTCTCTCGTOYGTTCCAGCTGTGAG . . Other Intron . . ENDGTHELIN2 440 T0.97 C 0.03 0.07 CCCCTGCAGACGTGYTCCAGACTGGCAAG TTC CTC Nonsynonymous PheLeu ENDGTHELIN2 556 G 0.99 A 0.01 0.02 ATGCGGGAGCCTCGRTCCACACATTCCAG CGGCGA Synonymous Arg Arg ENDGTHELIN2 976 A 0.84 G 0.16 0.27AGCCAGCCCTGGAGRCTGGATGGCTCCCC . . Other 3′UTR . ET1EX3 114 G 0.88 A 0.120.21 GCAACAGACCGTGARAATAGATGCCAATG GAG GAA Synonymous Glu Glu ETTEX5 90G 0.69 T 0.31 0.43 AAGCTGAAAGGCAAKCCCTCCAGAGAGCG AAG AAT NonsynonymousLys Asn GALNREX1 1052 G 0.94 T 0.06 0.11 CTGCCCACCTGGGTKCTGGGCGCCTTCATGTG GTT Synonymous Val Val GALNREX1 325 C 0.98 G 0.02 0.04GGTGCAGCACGCAGSCGCTCCGGGAGCCA . . Other Promoter . GALNREX1 327 G 0.81 C0.19 0.30 TGCAGCACGCAGCCSCTCCGGGAGCCAGG . . GALNREX1 553 G 049 C 0.510.50 TCTCTCAGAAGGTCSCGGCGCAAAGACGG . . Other Promoter . GALNREX1 887 C0.49 T 0.51 0.50 ATCTTCGCGCTGGGYGTGCTGGGCAACAG GGC GGT Synonymous GlyGly GALNREX3 298 A 0.68 G 0.32 0.43 TGATACTAAAGAAARTAAAAGTCGAATAG AATAGT Nonsynonymous Asn Ser GALNREX3 322 C 0.98 T 0.02 0.04AATAGACACCCCACYATCAACCAATTGTA CCA CTA Nonsynonymous Pro Leu GALNREX3 388T 0.98 C 0.02 0.04 AGTTTCCATATAAGYGGACCAGACACAGA . Other 3′UTR .GALNREX3 418 C 0.97 G 0.03 0.06 ACAAACAGAATGAGSTAGTAAGCGATGCT . . Other3′UTR . GALNREX3 523 G 0.98 T 0.02 0.04 TAGGAAATTCCTAGKTCTAGTGAGAATTA .. Other 3′UTR . GALNREX3 650 C 0.94 T 0.06 0.11TCCATATATATGTTYAACTCTTCATAGAT . . Other 3′UTR . GALNREX3 799 A 0.84 G0.16 0.26 ATGTATTTTAAAATRTGATCATGGACACA . . Other 3′UTR . GGREX1 125 G0.98 A 0.02 0.04 CTGCTGTTGCTGCTRCTGCTGGCCTGCCA CTG CTA Synonymous LeuLeu GGREX11 57 C 0.91 T 0.09 0.16 CACGAAGTGGTCTTYGCCTTCGTGACGGA TTC TTTSynonymous Phe Phe GGREX4 68 C 0.98 G 0.02 0.05GACCCCGGGGGCAGSCTTGGCGTGATGCC CCT GCT Nonsynonymous Pro Ala GGREX5 71 C0.83 G 0.17 0.28 CTGTCCCTGGGGGCSCTGCTCCTCGCCTT GCC GCG Synonymous AlaAla GGREX9 29 T 0.93 G 0.07 0.12 TGACAACATGGGCTKCTGGTGGATCCTGC TTC TGCNonsynonymous Phe Cys GHA1EX4 144 G 0.98 A 0.02 0.03CCTCTGACAGCAACRTCTATGACCTCCTA GTC ATC Nonsynonymous Val Ile GH2EX3 126 A0.94 T 0.06 0.12 CAACACCTTCCAACWGGGTGAAAACGCAG AGG TGG Nonsynonymous ArgTrp GHREX2 72 C 0.93 G 0.08 0.14 CTTCGCCGCCCTCASGATGACTACCTCTC . . Other5′UTR . GIPREX7 51 C 0.79 T 0.21 0.33 CATTGCACTAGAAAYTATATCCACATCAA AACAAT Synonymous Asn Asn GIPREX8 180 C 0.98 G 0.03 0.05GCTACTACCTGCTCSTCGGCTGGGGTCAG CTC GTC Nonsynonymous Leu Val GLUT2EX1 137C 0.32 A 0.68 0.44 CCACAGCACTAATTMTCTGTGGAGCAGAG . . Other Promoter .GLUT2EX1 164 T 0.31 C 0.69 0.43 AGTGCAGTGTGCCTYCCATGCTCCACAGC . . OtherPromoter . GLUT2EX1 237 T 0.96 C 0.04 0.07 AAAGATTTCTCTTTYCACCGGCTCCCAAT. . Other Promoter . GLUT2EX1 242 G 0.34 A 0.66 0.45TTTCTCTTTTCACCRGCTCCCAATTACTG . . Other Promoter . GLUT2EX10 161 G 0.99A 0.01 0.02 GAATTCCAAAAGAARAGTGGCTCAGCCCA AAG AAA Synonymous Lys LysGLUT2EX10 87 C 0.99 G 0.01 0.03 TCCTGGCCTTTACCSTGTTTACATTTTTT CTG GTGNonsynonymous Leu Val GLUT2EX10 92 T 0.35 C 0.65 0.46GCCTTTACCCTGTTYACATTTTTTAAAGTT TTT TTC Synonymous Phe Phe GLUT2EX3 250 C0.87 T 0.13 0.23 AGTTGGTGGAATGAYTGCATCATTCTTTG ACT ATT Nonsynonymous ThrIle GLUT2EX4A 153 T 0.96 C 0.04 0.08 TCAGGACTATATTGYGGTAAGTCTCACAC TGTTGC Synonymous Cys Cys GLUT2EX4A 162 T 0.83 A 0.17 0.28TATTGTGGTAAGTCWCACACACACACACA . . Other Intron . GLUT2EX4A 164 A 0.94 T0.06 0.11 TTGTGGTAAGTCTCWCACACACACACACA . . Other Intron . GLUT2EX4B 127A 0.28 G 0.72 0.40 CTGGCCATCGTCACRGGCATTCTTATTAG ACA ACG Synonymous ThrThr GLUT2EX5 78 C 0.93 T 0.08 0.14 ATCTGTGGCACATCYTGCTTGGCCTGTCT CTG TTGSynonymous Leu Leu GLUT2EX6 15 T 0.10 C 0.90 0.18TGTTTCAACCTGATYATTTTCTTGGACAG .. . Other Intron . GLUT2EX8 21 T 0.88 C0.12 0.21 TAATTTCTTTAAAAYTGTCCTAGGTATTC . . Other Intron . GLUT2EX8 38 T0.95 C 0.05 0.10 TCCTAGGTATTCCTYGTGGAGAAGGCAGG CTT CTC Synonymous LeuLeu GLUT4EX1 1002 A 0.99 C 0.01 0.02 CGTTGTGGGAACGGMATTTCCTGGCCCCC . .Other Promoter . GLUT4EX1 1051 C 0.74 T 0.26 0.38AGCATGTCGCGGACYCTTTAAGGCGTCAT . . Other Promoter . GLUT4EX1 1228 A 0.86T 0.14 0.24 TCTCAGGCCGCTGGWGTTTCCCCGGGGCA . . Other Promoter . GLUT4EX11632 A 0.71 C 0.29 0.42 CAGCCCCGCTCCACMAGATCCCCGGGAGC . . Other 5′UTR .GLUT4EX1 1662 A 0.64 G 0.36 0.46 CCACTGCTCTCCGGRTCCTTGGCTTGTGG . . Other5′UTR . GLUT4EX1 1683 G 0.98 C 0.02 0.05 GCTTGTGGCTGTGGSTCCCATCGGGCCCG .. Other 5′UTR . GLUT4EX1 1691 G 0.94 A 0.06 0.11CTGTGGGTCCCATCRGGCCCGCCCTCGCA . . Other 5′UTR . GLUT4EX1 368 G 0.96 A0.04 0.07 ACAGGAGGAATCGARCCTGACTTCTACCA . . Other Promoter . GLUT4EX1560 A 0.90 G 0.10 0.19 GCGGAAAGGCGAGARATAGTGGGTTGAGA . . Other Promoter. GLUT4EX1 615 G 0.93 A 0.07 0.14 TCGCTCGCCCTCCARGTGGCAGCACAACC . .Other Promoter . GLUT4EX1 91 C 0.95 T 0.05 0.10CAGGAGGTTTTGTTYACTCTGAAAAGGGA . . Other Promoter . GLUT4EX1 966 C 0.95 A0.05 0.10 CTGAAAGACAGGACMAAGCAGCCCGGCCA . . Other Promoter . GLUT4EX1019 C 0.94 G 0.06 0.11 TCCACCCTCCCTGTSTGGCCCCTAGGAGC . . Other Intron .GLUT4EX11 1005 G 0.83 A 0.17 0.28 GTGCTGGGATTACARGCGTGAGCCACCGC . .Other 3′UTR . GLUT4EX11 1099 A 0.95 C 0.05 0.10GAAAGTATGTGCCCMTGTGTGGCAAGATG . . Other 3′UTR . GLUT4EX11 791 T 0.93 C0.07 0.14 CGAGTGCAGTGGCGYGATCTTGCTTCACT . . Other 3′UTR . GLUT4EX11 827C 0.90 T 0.10 0.18 GTCTCCCAGGTTCAYGCCATTCTCCTGCC . . Other 3′UTR .GLUT4EX11 872 G 0.79 A 0.21 0.33 CTGGGACTACAGGCRCATGCCACCACACC . . Other3′UTR . GLUT4EX11 874 A 0.92 C 0.08 0.15 GGGACTACAGGCGCMTGCCACCACACCTG .. Other 3′UTR . GLUT4EX11 884 A 0.73 G 0.27 0.40GCGCATGCCACCACRCCTGGCTAATTTAT . . Other 3′UTR . GLUT4EX11 897 A 0.89 T0.11 0.20 CACCTGGCTAATTTWTTTTGTATTTTTAG . . Other 3′UTR . GLUT4EX11 930A 0.88 G 0.13 0.22 TACGCGGTTTCACCRTGTTAGCCAGAATG . . Other 3′UTR .GLUT4EX11 935 A 0.86 G 0.14 0.24 GGTTTCACCATGTTRGCCAGAATGGTCTC . . Other3′UTR . GLUT4EX11 941 A 0.49 G 0.51 0.50 ACCATGTTAGCCAGRATGGTCTCGATCTC .. Other 3′UTR . GLUT4EX11 963 C 0.96 T 0.04 0.07CGATCTCCTGACCTYGTGATCTGCCTGCC . . Other 3′UTR . GLUT4EX3 112 C 0.90 G0.10 0.17 TCCAGGCACCCTCASCACCCTCTGGGCCC ACC AGC Nonsynonymous Thr SerGLUT4EX4 96 C 0.71 T 0.29 0.42 ATGGGCCTGGCCAAYGCTGCTGCCTCCTA AAC AATSynonymous Asn Asn GLUT4EX7 19 C 0.95 T 0.05 0.09TCAGGCCTGACCTTYCCTTCTCCAGGTCT . . Other Intron . GLUT4EX7 227 G 0.99 C0.01 0.02 ATGCTGTATGTGTGSAGCAGCCTCCAGGC . . Other Intron . GLUT5EX1 184G 0.95 A 0.05 0.10 AAAAGGAGGTCAGCRGCACTCTGCCCTTC . . Other 5′UTR .GNB3EX1 184 A 0.89 C 0.11 0.20 GACAGATGGGGAACMCTGTGCCTCCCTGA . . OtherPromoter . GNB3EX1 201 A 0.63 G 0.37 0.47 GTGCCTCCCTGAACRGAAATGGCAGGGGA. Other Promoter . GNB3EX1 328 A 063 G 0.37 0.47GCCAGGGGCCAGTCRAGTGTATCACAGAT . . Other Promoter . GNB3EX10 144 G 0.93 A0.07 0.13 AGAGCATCATCTGCRGCATCACGTCCGTG GGC AGC Nonsynonymous Gly SerGNB3EX10 155 C 061 T 0.39 0.48 TGCGGCATCACGTCYGTGGCCTTCTCCCT TCC TCTSynonymous Ser Ser GNB3EX11 129 G 0.97 T 0.03 0.06CTTCCTCAAAATCTKGAACTGAGGAGGCT TGG TTG Nonsynonymous Trp Leu GNB3EX11 254C 0.75 T 0.25 0.38 CCACTAAGCTTTCTYCTTTGAGGGCAGTG . . Other 3′UTR .GNB3EX11 536 C 0.60 T 0.40 0.48 TATGGCTCTGGCACYACTAGGGTCCTGGC . . Other3′UTR . GSY1EX10 46 A 0.99 G 0.01 0.02 GGAGCCTTCCGGACRTGAACAAGATGCTG ATGGTG Nonsynonymous Met Val GSY1EX12 152 A 0.95 G 0.05 00.1GCCTTGGGGCTACACRCCGGGTGAGTGTAG ACA AGG Synonymous Thr Thr GSY1X12 163 G0.95 A 0.05 0.09 GAGAGCGGGTGAGTRTAGTGGGGAGGGGA . . Other intron GSY1EX1575 G 0.96 C 0.04 0.07 GCAAGGGCTTTCCASAGGACTTCAGGTAG GAG CAGNonsynonymous Glu Gln OSY1EX16 152 C 0.99 T 0.01 0.02CCGCTGGAGGAAGAYGGGGAGGGGTAGGA GAG GAT Synonymous Asp Asp GSY1EX16 210 C0.94 G 0.06 0.11 GCAACATCCGTGCASGAGAGTGGCCGCGG CCA GCA Nonsynonymous ProAla GSY1EX16 65 G 0.94 A 0.06 0.11 GGGCGAGGGTCGGTRCCAGGGTCGCGCTG GTG GTASynonymous Val Val GSY1EX2 219 G 0.99 A 0.01 0.03GTGCAAGGTGGGAGRTGGGGGAGGGGAGG . . Other Intron . GSY1EX3 117 A 0.95 G0.05 0.10 GGCTGGAGCGGTGGRAGGGAGAGGTCTGG AAG GAG Nonsyrtonymous Lys GluOSY1EX3 134 T 0.96 C 0.04 0.08 GGAGAGGTGTGGGAYACGTGCAACATGGG GAT GAGSynonymous Asp Asp OSY1EX3 149 A 0.95 G 0.05 0.01CAGCTGGAAGATGGGRGTGCGGTGGTACGA GGA GGG Synonymous Gly Gly GSYlEX3 53 C0.99 G 0.01 0.03 GGGCGCTGGGTGATSGAGGGAGGGCCTGT ATC ATG Nonsynonymous IleMet GSY1EX4 16 C 0.93 T 0.07 0.12 ACAGTGGGGCTGTGYGTGTTGGCGACAGT . .Other Intron . OSY1EX5 44 G 0.96 A 0.04 0.08TTCAAGGTGGACAARGAAGGAGGGGAGAG AAG AAA Synonymous Lys Lys GSY1EX6 54 A0.99 G 0.01 0.03 CGGGAATGGGGTGARTGTGAAGAAGTTTT AAT AGT Nonsynonymous AsnSer GSY1EX7 114 C 0.71 T 0.29 0.42 GGTGGTGAGGTGTTYCTGGAGGCATTGGG TTC TTTSynonymous Phe Phe OSY1EX7 16 T 0.98 G 0.02 0.04GCTTTAGGGTGCGTKGTGGGTTCTTTAGG . . Other Intron . OSY1EX7 17 G 0.99 C0.01 0.02 GTTTACGGTGGCTTSTGGGTTCTTTAGGC . . Other Intron . OSY1EX8 43 A0.94 G 0.06 0.11 GGTGAACGGCAGCGRGCAGACAGTGGTTG GAG GGG Nonsynonymous GluGly HAPTEX1 135 T 0.97 C 0.03 0.06 GATAAAGAGACAGAYTGATGGTTCCTGCC . .Other 5′UTR . HAPTEX1 188 C 0.90 T 0.10 0.18GATTTGAGGAAATAYTTTGGGAGGTTTGT . . Other 5′UTR . HAPTEX1 239 T 0.95 G0.05 0.09 CTTGGGATTTGTAAKAGAACATGAGAAGA . . Other 5′UTR . HAPTEX1 326 T0.45 A 0.55 0.50 ACTGGAAAAGATAGWGAGCTTAGCAGGGC . . Other 5′UTR . HAPTEX1329 C 0.76 G 0.24 0.37 GGAAAAGATAGTGASCTTAGCAGGGGCAA . . Other 5′UTR .HAPTEX1 369 A 0.88 C 0.12 0.21 ACAGGAATTAGGAAMTGGAGAAGGGGGAG . . Other5′UTR . HAPTEX1 375 A 0.89 G 0.11 0.19 ATTACGAAATGGAGRAGGGGGAGAAGTGA . .Other 5′UTR . HAPTEX4 34 A 0.53 G 0.47 0.50TTTGTTTCAGGAGTRTACACCTTAAATGA GTA GTG Synonymous Val Val HAPTEX6 34 G0.66 A 0.34 0.45 TTTGTTTCAGGAGTRTACACCTTAAACAA GTA GTG Synonymous ValVal HAPTEX7 1331 C 0.98 T 0.02 0.03 CATGCTGTTGCCTCYTCAAAGTGAATTAG . .Other 3′UTR . HAPTEX7 367 G 0.98 A 0.02 0.03GTGTCTGTTAATGARAGAGTGATGCCCAT GAG GAA Synonymous Glu Glu HAPTEX7 610 T0.98 C 0.02 0.04 CACACCTTCTGTGCYGGCATGTCTAAGTA GCT GCC Synonymous AlaAla HAPTEX7 673 C 0.98 T 0.02 0.03 GCCTTTGCCGTTCAYGACCTGGAGGAGGA CAC CATSynonymous His His HSD11KEX2 232 C 0.95 A 0.05 010ACCAAGGCCCACACMACCAGCACCGGTCA ACC ACA Synonymous Thr Thr HSD11KEX3 139 G0.83 A 0.18 0.29 AATTTCTTTGGCGCRCTCGAGCTGACCAA GCG GCA Synonymous AlaAla HSD11KEX 5951 T 0.96 A 0.04 0.08 ACTGTACTTCCCAAWTGCCACATTHAAA . .Other 3′UTR . HSTSCGENE 1392 C 0.97 T 0.03 0.06ATCTTCGGGGCCACYCTCTCCTCTGCCCT ACC ACT Synonymous Thr Thr HSTSCGENE 1881G 0.98 A 0.02 0.03 GCCCTCAGCTACTCRGTGGGCCTCAATGA TCG TCA Synonymous SerSer HSTSCGENE 2139 C 0.88 T 0.13 0.22 TCGGATGTCATTGCYGAGGACCTCCGCAG GCCGCT Synonymous Ala Ala HSTSCGENE 2595 C 0.90 T 0.10 0.18CGTGTGTTCGTAGGYGGCCAGATTAACAG GGC GGT Synonymous Gly Gly HSTSCGENE 3269G 0.81 A 0.19 0.30 GGTCTTGTGTTTATRGGCTAGAGAAATAG . . Other 3′UTR .HSTSCGENE 3660 C 0.94 T 0.06 0.11 CTGCAACCTCCTCCYGGGTTCAAGCATTT . Other3′UTR . HSTSCGENE 3710 G 0.98 C 0.02 0.03 TAGCTGGGATTACASGCACCTGCCATCAC. Other 3′UTR . HSTSCGENE 3727 C 0.69 G 0.31 0.43ACCTGCCATCACACSAGCTAATTTTTGTA . Other 3′UTR . HSTSCGENE 3838 G 0.90 A0.10 0.18 CCCAAAGTGCTGGGRTTACAGGCCTGAGC . Other 3′UTR . HUMAPNH1A 3057 T0.92 C 0.08 0.15 AGGGCATCTCTGAGYGTCTCTGCCTGGAG . . Other 3′UTR . HUMOFAT2930 T 0.65 G 0.35 0.45 ATCTCCTAAAAGTGKTTTTTATTTCCTTG . Other 3′UTR .HUMGLUTRN 2110 G 0.94 C 0.06 0.12 GGCTATGGCCACCCSTTCTGCTGGCCTGG . Other3′UTR . HUMGLUTRN 933 A 0.99 C 0.01 0.02 GATGATGCGGGAGAMGAAGGTCACCATCCAAG ACG Nonsynonymous Lys Thr HUMGUANCYC 2388 C 0.93 T 0.07 0.14ATTGTCACTGAATAYTGTCCTCGTGGGAG TAC TAT Synonymous Tyr Tyr HUMGUANCYC 2571A 0.86 G 0.14 0.24 CGTTTTGTGCTCAARATCACAGACTATGG AAA AGA NonsynonymousLys Arg HUMGUANCYC 2643 G 0.93 A 0.07 0.14 GCCCTCTATGCCAARAAGCTGTGGACTGCAAG AAA Synonymous Lys Lys HUMGUANCYC 2787 C 0.93 G 0.07 0.13GAGGGCCTGGACCTSAGCCCCAAAGAGAT CTC CTG Synonymous Leu Leu HUMGUANCYC 2905C 0.97 G 0.03 0.07 AGCGATGTTGGGCTSAGGACCCAGCTGAG CAG GAG NonsynonymousGln Glu HUMGUANCYC 3300 C 0.81 G 0 19 0.31 GACAACTTTGATGTSTACAAGGTGGAGACGTC GTG Synonymous Val Val HUMGUANCYC 3663 G 0.96 A 0.04 0.08CTTCGGGGGGATGTRGAAATGAAGGGAAA GTG GTA Synonymous Val Val IAPPEX1-2 199 T0.97 C 0.03 0.06 TTTATTTAGAGAAAYGCACACTTGGTGTT . . Other Intron .IAPPEX1-2 358 A 0.99 C 0.01 0.02 GACTGTATCAATAAMAATTTTGATCCTTG . . OtherIntron . IAPPEX3 1050 T 0.83 C 0.18 0.29 TAAAGTCTATTGTTYGTTGTGCTTGCTGG .. Other 3′UTR . IAPPEX3 1076 T 0.75 A 0.25 0.38TGGTACTAAGAGGCWATTTAAAAGTATAA . . Other 3′UTR . IAPPEX3 1184 A 0.66 C0.34 0.45 TTTAAGTGGCTTTCMGCAAACCTCAGTCA . . Other 3′UTR . IAPPEX3 296 C0.85 T 0.15 0.26 TGCCCTTTTCATCTYCAGTGTGAATATAT . . Other 3′UTR . IAPPEX3848 G 0.11 A 0.89 0.19 CTCCAGCCTGGGTGRCAGAGTGAGACTCG . . Other 3′UTR .IAPPEX3 959 A 0.93 G 0.07 0.13 TTCCTTTTTGCAGTRTATTTCTGAAATGA . . Other3′UTR . ICAM1EX1 683 A 0.66 C 0.34 0.45 AGAGTTGCAACCTCMGCCTCGCTATGGCT .. Other Promoter . ICAM1EX2 115 A 0.70 T 0.30 0.42CTGTGACCAGCCCAWGTTGTTGGGCATAG AAG ATG Nonsynonymous Lys Met ICAM1EX3 151G 0.99 C 0.01 0.02 CTCCGTGGGGAGAASGAGCTGAAACGGGA AAG AAC NonsynonymousLys Asn ICAM1EX4 115 C 0.92 T 0.08 0.15 TGTTCCCTGGACGGKCTGTTCCCAGTCTCGGG GGT Synonymous Gly Gly ICAM1EX4 238 C 0.95 T 0.05 0.10GTGACCGCAGAGGAYGAGGGCACCCAGCG GAC GAT Synonymous Asp Asp ICAM1EXS 47 G0.99 A 0.01 0.02 TTCCGGCGCCCAACRTGATTCTGACGAAG GTG ATG Nonsynonymous ValMet ICAM1EX6 18 G 0.94 A 0.06 0.12 CATGTCATCTCATCRTGTTTTTCCAGATG . .Other Intron . ICAM1EX6 254 G 0.45 A 0.55 0.50GGGAGGTCACCCGCRAGGTGACCGTGAAT GAG AAG Nonsynonymous Glu Lys ICAM1EX6 39G 0.95 A 0.05 0.10 TCCAGATGGCCCCCRACTGGACGAGAGGG CGA CAA NonsynonymousArg Gln 1CAM1EX7 304 C 0.99 T 0.01 0.03 GCAGCTACACCTACYGGCCCTGGGACGCC .. Other 3′UTR . ICAM1EX7 869 A 0.99 G 0.01 0.03TGGCAAAAAGATCARATGGGGCTGGGACT . . Other 3′UTR . ICAM1EX7 929 T 0.96 C0.04 0.07 GAGTGATTTTTCTAYCGGCACAAAAGCAC . . Other 3′UTR. ICAM2EX1 300 C0.99 T 0.01 0.02 GAGATGTCCTCTTTYGGTTACAGGACCCT TTC TTT Synonymous PhePhe ICAM2EX2 63 G 0.93 A 0.07 0.13 GGCCAAAGAAGCTGRCGGTTGAGCCCAAA GCG ACGNonsynonymous Ala Thr ICAM2EX3 281 G 0.98 A 0.03 0.05GGACTTGATGTCTCRCGGTGGCAACATCT CGC CAC Nonsynonymous Arg His INSEX1 233 T0.39 A 0.61 0.48 CAGCCCTGCCTGTCWCCCAGATCACTGTC . . Other 5′UTR . INSEX1247 C 0.97 T 0.03 0.06 TCCCAGATCACTGTYCTTCTGCCATGGCC . . Other 5′UTR .INSEX1 453 C 0.78 T 0.22 0.34 CAGGGTGAGCCAACYGCCCATTGCTGCCC . . OtherIntron . INSEX2 14 C 0.99 T 0.01 0.02 GAACCTGCTCTGCGYGGCACGTCCTGGCA . .Other Intron . KALSTEX1 133 G 0.88 T 0.12 0.21CTGCTCCTCCTGCTKGTTGGACTACTGGC CTG CTT Synonymous Leu Leu KALSTEX1 511 A0.89 G 0.11 0.19 CATGGGCTGGAAACRCGCGTGGGCAGTGC ACA ACG Synonymous ThrThr KALSTEX2 318 A 0.67 T 0.33 0.44 GTAATCAGTGTGCTWTGGGGGCTGAATCT . .Other Intron . KALSTEX2 79 C 0.72 T 0.28 0.40ACTCCCAAAGACTTYTATGTTGATGAGAA TTC TTT Synonymous Phe Phe KALSTEX3 17 A0.98 G 0.02 0.05 AATGTTCTAACTCARTGCCCCTTTCAGGA . . Other Intron .KALSTEX3 91 T 0.97 C 0.03 0.07 CTGGCTCCTATGTAYTAGATCAGATTTTG TTA CTASynonymous Leu Leu KLKEX1 105 G 0.98 T 0.02 0.03AGGGCATTCTGAAGKCCAAGGCTTATATT . . Other 5′UTR . KLKEX3 253 C 0.68 G 0.320.44 TGGAGTTGCCCACCSAGGAACCCGAAGTG CAG GAG Nonsynonymous Gln Glu KLKEX350 G 0.98 A 0.02 0.03 GCTCTGGCTGGGTCRCCACAACTTGTTTG CGC CACNonsynonymous Arg His KLKEX4 110 T 0.97 A 0.03 0.07CCACGTCCAGAAGGWGACAGACTTCATGC GTG GAG Nonsynonymous Val Glu KLKEX4 88 A0.66 G 0.34 0.45 CTAATGATGAGTGCRAAAAAGCCCACGTC AAA GAA Nonsynonymous LysGlu KLKEX5 318 A 0.75 G 025 0.38 CCCCAGCTGTGTCARTCTCATGGCCTGGA . . Other5′UTR . MRLEX1B 156 T 0.46 C 0.54 0.50 GCCGATCAGCCAATAYTGGACTTGCTGGTG .. Other 5′UTR . MRLEX1B 16 G 0.90 C 0.10 0.18GGGCGGGTGCCCGCSTCCCCCTCTGCGCG . . Other 5′UTR . MRLEX2 1338 A 0.97 C0.03 0.05 CTCTTTTAAAGGGAMTCCAACAGTAAACC AAT ACT Nonsynonymous Asn ThrMRLEX2 1405 T 0.99 C 0.01 0.03 GATGATAAAGACTAYTATTCCCTATCAGG TAT TACSynonymous Tyr Tyr MRLEX2 1617 G 0.99 A 0.01 0.03AATATCTTTATCACRATCGGCTAGAGACC CGA CAA Nonsynonymous Arg Gln MRLEX2 1668A 0.97 G 0.03 0.05 CTTTCCTCCTGTCARTACTTTAGTGGAGT AAT AGT NonsynonymousAsn Ser MRLEX2 1696 C 0.97 T 0.03 0.06 TCATGGAAATCACAYGGCGACCTGTCGTC CACCAT Synonymous His His MRLEX2 1720 T 0.50 C 0.50 0.50TCGTCTAGAAGAAGYGATGGGTATCCGGT AGT AGC Synonymous Ser Ser MRLEX9 1326 C0.99 T 0.01 0.03 GGAATGACACACTGYGGTGTCTGCAGCTC . . Other 3′UTR . MRLEX91572 A 0.43 G 0.57 0.49 GTTAAAGATCAGCTRTTCCCTTCTGATCT . . Other 3′UTR .MRLEX9 1670 A 0.88 G 0.13 0.22 GGCCCATCTTGGCARGGTTCAGTCTGAAT . . Other3′UTR . MRLEX9 1964 G 0.86 A 0.14 0.24 AATCTTTTAAAAATRATGATAATCATCAG . .Other 3′UTR . MRLEX9 247 T 0.97 C 0.03 0.06ACCTGTTTTTAACAYGTGATGGTTGATTC . . Other 3′UTR . MRLEX9 2551 T 0.88 C0.13 0.22 CCAAATTGTCTGTCYGCTCTTATTTTTGT . . Other 3′UTR . MRLEX9 2635 G0.36 A 0.64 0.46 TCATATAATTTAAARAAACACTAAATTAG . . Other 3′UTR . MRLEX9869 C 0.99 G 0.01 0.02 TTTGCTGTGCTGTASATTACTGTATGTAT . . Other 3′UTR .MRLEX9 916 A 0.83 C 0.18 0.29 AATAAGGTATAAGGMTCTTTTGTAAATGA . . Other3′UTR . NCX1EX12 1135 A 0.57 G 0.43 0.49 AGATTCCCAGGAACRTGCAAAATCCTTTC .. Other 3′UTR . NCX1EX12 1190 C 0.80 T 0.20 0.32TGATTGGCAAGGTCYTTCTTCCAGCATTC . . Other 3′UTR . NCX1EX12 1298 A 0.99 G0.01 0.03 ATAACCCCATTCAARAAGCACATCATCGT . . Other 3′UTR . NCX1EX12 1366G 0.99 C 0.01 0.03 CGTTGCTTGGGATTSTCTGTCAGTTTTAT . . Other 3′UTR .NCX1EX12 1407 A 0.84 G 0.16 0.26 CCATGGCTTGCACARTCCTGTTCCAGTCA . . Other3′UTR . NCX1EX12 1841 G 0.97 C 0.03 0.06 ACCCATTAATTCAGSAAGGCCAAGGAGAA .. Other 3′UTR . NCX1EX12 2099 T 0.94 C 0.06 0.11GAAAGAAGCCAGGGYGACCAACGGGCCTT . . Other 3′UTR . NCX1EX12 2123 T 0.70 Del0.30 0.42 GCCTTTAAAAGTGTTGTCTCCTCTACTTA . . Other 3′UTR . NCX1EX12 2614T 0.96 C 0.04 0.08 TGTGATTACTATTTYCATGAGTAAAAGTG . . Other 3′UTR .NCX1EX12 2810 G 0.67 A 0.33 0.44 TTTATCTTTGACCGRCTTGCAGATAAATA . . Other3′UTR . NCX1EX12 2832 C 0.99 G 0.01 0.03 ATAAATATATCTCTSCATTTTAAACCAAG .. Other 3′UTR . NCX1EX12 3079 A 0.66 C 0.34 0.45TAAACATTAGAAAAMTTTTTGCACTCATT . . Other 3′UTR . NCX1EX12 3193 G 0.99 C0.01 0.03 TTGAAAGCTTTTTGSTTTGTTTGCTTTTT . . Other 3′UTR . NCX1EX12 664 T0.99 C 0.01 0.03 TCTCTCCAGGTTGAYAAATCCTTAAGGCT . . Other 3′UTR .NCX1EX12 709 A 0.94 G 0.06 0.10 TTGGTTTTGTTTTCRGTGGAGCTGGGGAG . . Other3′UTR . NCX1EX12 948 G 0.89 A 0.11 0.20 AGCATGCTTCATCRTATTACCAAAGTTC . .Other 3′UTR . NCX1EX4 59 G 0.99 A 0.01 0.03TAGAATATTTGACCRTGAGGAATATGAGA CGT CAT Nonsynonymous Arg His NCX1EX9 66 A0.97 T 0.03 0.06 ACTGACCAGCAAAGWGGAAGAGGAGAGGC . . Other Intron .NETEX11 123 T 0.86 G 0.14 0.24 CGTCAGTCCTGCCTKCCTCCTGGTGTGTA TTC TGCNonsynonymous Phe Cys NETEX12 81 T 0.93 C 0.07 0.13TCACCTACGACGACYACATCTTCCCGCCC TAC CAC Nonsynonymous Tyr His NETEX13 50 G0.93 A 0.07 0.12 GCCTATGGCATCACRCCAGAGAACGAGCA ACG ACA Synonymous ThrThr NETEX14 29 G 0.93 C 0.07 0.14 TGTCTTTCTCTGCASTTGCAACACTGGCT . .Other Intron . NETEX5 121 A 0.93 C 0.07 0.12CTCCAATGGCATCAMTGCCTACCTGCACA AAT ACT Nonsynonymous Asn Thr NETEX5 175 A0.96 G 0.04 0.07 CACGGTCAGTGCTCRGTGACCACCAAGCC . . Other Intron . NETEX583 C 0.95 G 0.05 0.10 TTCGTGCTCCTGGTSCATGGCGTCACGCT GTC GTG SynonymousVal Val NETEX7 112 G 0.92 C 0.08 0.15 TCCTTGGTTACATGSCCCATGAACACAAG GCCCCC Nonsynonymous Ala Pro NETEX7 131 A 0.93 G 0.07 0.14TGAACACAAGGTCARCATTGAGGATGTGG AAC AGC Nonsynonymous Asn Ser NETEX7 73 G0.94 C 0.06 0.11 GTATCACCAGCTTCSTCTCTGGGTTCGCC GTC CTC Nonsynonymous ValLeu NETEX8 17 C 0.55 A 0.45 0.49 TGATGAGGTCCTTGMTGTTTCTTACAGGA . OtherIntron . NETEX9 157 A 0.91 G 0.09 0.16 GTTCTGCATAACCARGGTGAGTAG0GGCT AAGAGG Nonsynonymous Lys Arg NETEX9 56 G 0.96 A 0.04 0.07GAGGCTGTCATCACRGGCCTGGCAGATGA ACG ACA Synonymous Thr Thr NPYEX1 112 G0.97 A 0.03 0.06 GCGCTGGCCGAGGCRTACCCCTCCAAGCC GCG GCA Synonymous AlaAla NPYEX1 178 A 0.90 G 0.10 0.18 GCCAGATACTACTCRGCGCTGGGACACTA TCA TCGSynonymous Ser Ser NPYEX1 92 C 0.95 A 0.05 0.10GCCCTGCTCGTGTGCMTGGGTGCGCTGGCC CTG ATG Nonsynonymous Leu Met NPYEX2 45 T0.40 C 0.60 0.48 TATGGAAAACGATCYAGCCCAGAGACACT TCT TCC Synonymous SerSer NPYEX3 100 A 0.96 G 0.04 0.08 CCTATTTTCAGCCCRTATTTCATCGTGTA . .Other 3′UTR . NPYEX3 78 G 0.91 T 0.09 0.16 GAGACTTGCTCTCTKGCCTTTTCCTATTT. . Other 3′UTR . NPYR1EX2 144 T 0.94 G 0.06 0.12AACATACTGTCCATKTGTCTAAAATAATC . . Other 5′UTR . NPYR1EX3 451 A 0.94 C0.06 0.12 AGTCGCATTTAAAAMAATCAACAACAATG AAA ACA Nonsynonymous Lys ThrPG1SEX1 196 C 0.99 A 0.01 0.03 GCATATAATCTCTTMCTTCCTGTAAATCC . . OtherPromoter . PG1SEX1 396 T 0.82 G 0.18 0.30 TGCGGGGAGCAGGGKTTCTCCCAGAGCGC. . Other Promoter . PG1SEX1 419 G 0.95 A 0.05 0.09GAGCGCCCCGGTCCRACCCCTGCGGACCT . . Other Promoter . PG1SEX1 568 C 0.93 T0.07 0.12 CCCCGCCAGCCCCGYCAGCCCCGCCAGCC . . Other 5′UTR . PG1SEX1 636 C0.98 T 0.02 0.04 CACTGTTGCTGCTGYTGCTACTGAGCCGC CTG TTG Synonymous LeuLeu PG1SEX10 1255 C 0.95 T 0.05 0.09 TTCTGCATTCACAGYGSCTCCTGGRCCTG . .Other 3′UTR . PG1SEX10 149 C 0.99 T 0.01 0.03GCTACCGCATCCGCYCATGACACAGGGAG CCA TCA Nonsynonymous Pro Ser PG1SEX101500 C 0.84 T 0.16 0.28 CCTGGCCAACATGGYGAAACCCCGTCTCT . . Other 3′UTR .PG1SEX10 1505 C 0.97 T 0.03 0.06 CCAACATGGCGAAAYCCCGTCTCTACTAA . . Other3′UTR . PG1SEX10 1521 C 0.94 A 0.06 0.11 CCGTCTCTACTAAAMATAAAAAAATTAGT .. Other 3′UTR . PG1SEX10 1525 A 0.66 C 0.34 0.45CTCTACTAAACATAMAAAAATTAGTCAGG . . Other 3′UTR . PG1SEX10 1544 G 0.65 C0.35 0.45 ATTAGTCAGGTGTGSCGGTGCCGTGCCTG . . Other 3′UTR . PG1SEX10 1760T 0.99 G 0.01 0.02 TTATGATGCTATTTKTATTAATATAAAGT . . Other 3′UTR .PG1SEX10 1776 C 0.99 T 0.01 0.02 ATTAATATAAAGTCYTGTTTATTGAGACC . . Other3′UTR . PG1SEX10 1852 A 0.91 G 0.09 0.16 CAGCATCTCTATGARGAGAAGGAGGGTTG .. Other 3′UTR . PG1SEX10 2474 C 0.90 T 0.10 0.19CGCAGGCTGCAACCYTGGTGTGCTGGGCG . . Other 3′UTR . PG1SEX10 2636 T 0.48 C0.52 0.50 ACTCAAGGAAAAGAYGTGCTCCCACCAGG . . Other 3′UTR . PG1SEX10 270 T0.99 C 0.01 0.03 GCTAGCATTACCACYTCCCTGCTTTTCTC . . Other 3′UTR .PG1SEX10 2967 C 0.98 T 0.02 0.04 TTGAGATGGAGTCTYGCTCTGCTGCCCAG . . Other3′UTR . PG1SEX10 2974 C 0.52 T 0.48 0.50 GGAGTCTCGCTCTGYTGCCCAGGCTAGAG .. Other 3′UTR . PG1SEX10 3009 T 0.91 C 0.09 0.17GGCGTGATCTCGGCYCACTGCAAGCTCTG . . Other 3′UTR . PG1SEX10 3022 T 0.77 C0.23 0.35 CTCACTGCAAGCTCYGCCTCCCGTGTTCA . . Other 3′UTR . PG1SEX10 3061T 0.69 C 0.31 0.43 CTGCCTCAGCCTCCYGAGTAGCTGGGACT . . Other 3′UTR .PG1SEX10 308 G 0.95 T 0.05 0.10 TGGGTCCAGGGGAGKGAAAAGCTAAGAGG . . Other3′UTR . PG1SEX10 3082 A 0.88 G 0.12 0.21 CTGGGACTACAGGCRCCCGCCACCACACC .. Other 3′UTR . PG1SEX10 3139 A 0.88 G 0.13 0.22TGGGATTTCACCGTRTTAGCCAGGATGGT . . Other 3′UTR . PG1SEX10 3140 T 0.82 C0.18 0.30 GGGATTTCACCGTAYTAGCCAGGATGGTC . . Other 3′UTR . PG1SEX10 3186C 0.90 T 0.10 0.17 TGATCTGCCCGCCTYGGCCTCCCAAAGTG . . Other 3′UTR .PG1SEX10 3214 T 0.88 C 0.12 0.21 GCTGGGATTACAGGYGTGAGCCACCGC0C . . Other3′UTR . PG1SEX10 3217 G 0.88 A 0.12 0.20 GGGATTACAGGTGTRAGCCACCGCGCCCA .. Other 3′UTR . PG1SEX10 3244 A 0.98 C 0.02 0.04CAGCCAAGAATAAAMTACTCTTAAGTTGA . . Other 3′UTR . PG1SEX10 3339 C 0.99 T0.01 0.03 GTTTACCAAATATTYTCCTTTAAACAGAC . . Other 3′UTR . PG1SEX10 3419G 0.95 A 0.05 0.10 GCCCAGGCTGGAGTRCAATGGCACGA1CI . . Other 3′UTR .PG1SEX10 3540 A 0.98 T 0.02 0.04 CAACTGGTTTTTGTWTTTTTAGTAGAGAC . . Other3′UTR . PG1SEX10 3651 G 0.91 A 0.09 0.16 GATTACAGGCATGARCCACCATGCCCGGC .. Other 3′UTR PG1SEX10 3663 G 0.94 A 0.06 0.11GAGCCACCATGCCCRGCCTAAACTTTGTT . . Other 3′UTR . PG1SEX10 3774 C 0.85 T0.15 0.26 ATGAAAAATAAATTYGCTGGGGAAGGGGG . . Other 3′UTR . PG1SEX10 3840C 0.73 T 0.27 0.40 TCTCTGTTACAAAAYGAGATAAGCAAGTR . . Other 3′UTR .PG1SEX10 400 C 0.98 T 0.02 0.05 TCAGGCTFFGTCTGYTCCCAAITCACCTC . . Other3′UTR PGISEX10 4074 A 0.96 G 0.04 0.07 GATTTTAATGATTARAAAGAAIAAACACA . .Other 3′UTR . PG1SEX10 454 T 0.98 C 0.02 0.04AAATGCTATTCAGAYAAGGCAGAACTAGG . . Other 3′UTR . PG1SEX10 573 G 0.99 T0.01 0.02 GGATGCTGGCCACAKAAAGGCCACTCAGG . . Other 3′UTR . PG1SEX10 578 G0.99 A 0.01 0.02 CTGGCCACAGAAAGRCCACTCAGGATGTC . . Other 3′UTR .PG1SEX10 948 C 0.99 A 0.01 0.02 CTCCTTAGACTGATMAAGCCAAAAAAGAA . . Other3′UTR . PG1SEX3 165 T 0.98 A 0.02 0.05 CATTACAGCCCCAGWGATGAAAAGGCCAG AGTAGA Nonsynonymous Ser Arg PG1SEX3 69 6 0.98 T 0.02 0.05TCCTACGACGCGGTKGTGTGGGAGCCTCG GTG GTT Synonymous Val Val PG1SEX4 143 T0.96 C 0.04 0.07 ACTTCTCCIACAGCYICCTGCTCAGGTGA TTC CTC Nonsynonymous PheLeu PG1SEX4 93 A 0.99 C 0.01 0.02 GGGCGATGCTACAGMAGCAGGCAGTGGCT GAA GCANonsynonymous Glu Ala PG1SEX5 79 C 0.99 T 0.01 0.02CAGGCCCAGGACCGYGTCCACTCAGCTGA CGC CGT Synonymous Arg Arg PG1SEX6 35 C0.98 T 0.02 0.05 GCAGTGTCAAAAGTYGCCTGTGGAAGCTG CGC TGC Nonsynonymous ArgCys PG1SEX6 52 A 0.98 G 0.02 0.05 CTGTGGAAGCTGCTRTCCCCAGCCAGGCT CTA CTGSynonymous Leu Leu PG1SEX6 97 G 0.90 A 0.10 0.18CGGAGCAAATGGCTRGAGAGTTACCTGCT CTG CTA Synonymous Leu Leu PG1SEX8 102 A0.26 C 0.74 0.38 CCATGGCAGACGGGMGAGAATTCAACCTG AGA CGA Synonymous ArgArg PG1SEX9 42 C 0.99 T 0.01 0.02 TTCCTGAACCCTGAYGGATCAGAGAAGAA GAC GATSynonymous Asp Asp PLA2AEX1 302 T 0.96 A 0.04 0.07CCCCGCAGTCTCAAWTCGAGGTTCCCAGT . . Other Intron . PLA2AEX2 118 C 0.95 T0.05 0.10 GGGAGTGACCCCTTYTTGGAATACAACAA TTC TTT Synonymous Phe PhePLA2AEX2 42 A 0.95 C 0.05 0.10 CAGTGGCCGCCGCCGMCAGCGGCATCAGCC GAC GCCNonsynonymous Asp Ala PLA2AEX3 103 A 0.95 C 0.05 0.10ATTTCTGCTGGACAMCCCGTACACCCACA AAC ACC Nonsynonymous Asn Thr PLA2AEX3 104C 0.89 A 0.11 0.20 TTTCTGCTGGACAAMCCGTACACCCACAC AAC AAA NonsynonymousAsn Lys PLA2AEX3 131 G 0.91 A 0.09 0.17 ACCTATTCATACTCRTGCTCTGGCTCGGCTCG TCA Synonymous Ser Ser PLA2AEX3 59 C 0.60 T 0.400.48CATGACAACTGCTAYGACCAGGCCAAGAA TAC TAT Synonymous Tyr Tyr PNMTEX3 181A 0.89 T0 11 0.19 GCTTGGAGGCTGTOWOCCCAGATCTTGCC AGC TGC NonsynonymousSer Cys PNMTEX3 251 T 0.89 A 0.11 0.19 GCCTGGGGGGCACCWCCTCCTCATCGGGG CTCCAC Nonsynonymous Leu His PNMTEX3 269 T 0.93 A 0.08 0.14CCTCATCGGGGCCCWGGAGGAGTCGTGGT CTG CAG Nonsynonymous Leu Gln PNMTEX3 380G 0.96 A 0.04 0.08 GGTCCGGGACCTCCRCACCTATATCATGC CGC CAC NonsynonymousArg His PNMTEX3 445 T 0.96 A 0.04 0.08 GCGTCTTCTTCGCCWGGGCTCAGAAGGTT TGGAGG Nonsynonymous Trp Arg PNMTEX3 554 C 0.88 T 0.13 0.22AAATAATACCCTGCYGCTGCGGTCAGTGC . . Other 3′UTR . PNMTEX3 75 A 0.96 G 0.040.08 CGAGCCAGGGTGAARCGGGTCCTGCCCAT AAA AAG Synonymous Lys Lys PPGLGCEX1133 G 0.98 A 0.02 0.05 CAGGTATTAAATCCRTAGTCTCGAACTAA . . Other Intron .PPGLGCEX1 44 C 0.99 T 0.01 0.03 ATGAAAAGCATTTAYTTTGTGGCTGGATT TAC TATSynonymous Tyr Tyr PPGLGCEX1 560 C 0.99 T 0.01 0.03AAGTACTCAAAATTYCTCTGTCCAAAGAA . . Other Intron . PPGLGCEX1 635 T 0.92 A0.08 0.15 ACGTAAACTGTACAWAAATATCTCTTGGC . . Other Intron . PPGLGCEX2 196G 0.93 A 0.07 0.14 AGAGGAACAGGTAARAGTCTAAGCCTGGC . . Other Intron .PPGLGCEX3 119 C 0.99 T 0.01 0.02 TTTGGAAGGCCAAGYTGCCAAGGAATTCA GAT GTTNonsynonymous Ala Val PPGLGCEX4 447 A 0.99 T 0.01 0.02AAATGAAACATGGGWAATGTTACATCATT . . Other 3′UTR . PPGLGCEX4 571 C 0.96 T0.04 0.07 TAGTGAGAACTGGAYACCGAAAAATACTT . . Other 3′UTR . PPGLGCEX4 615T 0.70 C 0.30 0.42 GATTTTTTAATAATYATTCATAATTGTTT . . Other 3′UTR .PPGLGCEX4 672 T 0.98 C 0.02 0.04 AAATAATCTTTAAAYGAAAATATTTTAAG . . Other3′UTR . PPTHREX1 106 C 0.96 G 0.04 0.08 CCCCGGATCCCGGASCCATCCTGTGGAGC .. Other 5′UTR . PPTHREX1 36 G 0.99 C 0.01 0.02AGAGGGCTCGCCAGSCGCCCGGGGTCCTC . . Other 5′UTR . PPTHREX2 19 G 0.95 A0.05 0.09 AACCCAGACGCCGCRATGCCCGGCCCTTG . . Other 5′UTR . PPTHREX2 41 C0.96 G 0.04 0.08 GCCCTTGGTTGCTGSTCGCTCTGGCTTTG CTC GTC Nonsynonymous LeuVal PPTHREX2 79 C 0.99 G 0.01 0.02 CTGACCGGTGTCCCSOOCGGCCGTGCTCA CCC CCGSynonymous Pro Pro PPTHREX3 1234 C 0.97 G 0.03 0.06TAATGATAATAAAASCTGCATCCAGATAA . . Other 3′UTR . . PPTHREX3 185 T 0.91 C0.09 0.16T CATGGTCAGTCGAYGTAACCCAGCACAA GAT GAC Synonymous Asp AspPPTHREX3 401 G 0.95 A 0.05 0.09 CCCTGTGGGCCCCARGGAGCCTATGGTCA CAG CAASynonymous Gln Gln PPTHREX3 425 C 0.90 T 0.10 0.18GGTCAAGCGGGCCTYCTGCTGGGGCTCCT CTC CTT Synonymous Leu Leu PPTHREX3 512 G0.90 A 0.10 0.19 GCAGCCTGGGTCAGRGAGCCCCTGGAGGA AGG AGA Synonymous ArgArg PPTHREX3 576 A 0.91 G 0.09 0.16 CTAAGGATGTCTTGRGCCCTGTGTGCCCC . .Other 3′UTR . PPTHREX3 895 C 0.99 A 0.01 0.03AGCCCCTGGGAGGGMAGCCAGTGAGGGTG . . Other 3′UTR . PPTHREX3 963 G 0.98 C0.02 0.05 CCCCTCCCCAACCTSGCAGGATTCTCCAT . . Other 3′UTR . PTGER3EX1 232C 0.96 T 0.04 0.08 TGCGGCTCTCTGGAYGCCATCCCCTCCTC . . Other 5′UTR .PTGER3EX1 371 C 0.96 G 0.04 0.07 GCGCGGGGCAACCTSACGCGCCCTCCAGG CTC CTGSynonymous Leu Leu PTGER3EX1 765 A 0.98 T 0.02 0.04GGTATGCGAGCCACWTGAAGACGCGTGCC ATG TTG Nonsynonymous Met Leu PTGER3EX1878 G 0.90 T 0.10 0.18 CAGTGGCCCGGGACKTGGTGCTTCATCAG ACG ACT SynonymousThr Thr PTGER3EX10 206 T 0.98 C 0.03 0.05 ACATGTTTTTGTACYTTTACTATATCTAC. . Other 3′UTR . PTGER3EX10 281 A 0.85 G 0.15 0.26GCGTATACATTATCRTATGTAAAATTTGC . . Other 3′UTR . PTOER3EX2 1293 T 0.38 C0.62 047 ACTAAAATGTTTTTYCTACAGTCTACATG . . Other Intron . PTGER3EX2 1295T 0.86 C 0.14 0.23 TAAAATGTTTTTTCYACAGTCTACATGAA . . Other Intron .PTGER3EX2 1393 T 0.84 C 0.16 0.27 GCACTTCTTAAAAAYGTCTCCCCACCAAA . .Other Intron . PTGER3EX2 1403 C 0.98 A 0.03 0.05AAAATGTCTCCCCAMCAAACATAGTAATC . . Other Intron . PTGER3EX2 1614 T 0.94 C0.06 0.11 TAAAGAATTAATTTYGATAGGTACAATAT . . Other Intron . PTGER3EX21719 G 0.98 C 0.03 0.05 TGGAGACAAAATCTSTTGAGAGTGCTTAT . . Other Intron .PTGER3EX2 2153 A 0.99 G 0.01 0.03 AGTCCATCAGGCTGRTAAAGTGAATTATT . .Other Intron . PTGER3EX2 2517 T 0.92 C 0.08 0.15TAGGCATTCGTTAGYATGGGGAAACCTGA . . Other Intron . PTOER3EX2 3069 T 0.93 C0.08 0.14 TAGTGCTGTATATAYCCCAAGATATTTTA . . Other Intron . PTGER3EX23101 A 0.91 G 0.09 0.17 AAATGTAAGTGTTTRATCATGCCAGATTT . . Other Intron .PTGER3EX2 326 T 0.91 A 0.09 0.17 ATATCGCTAAACCTWACTGTGAATTTAGG . . OtherIntron . PTGER3EX2 3282 A 0.98 G 0.03 0.05 ACTAAAAACTGGCARACAGTATTTTAATA. . Other Intron . PTGER3EX2 3382 T 0.63 C 0.37 0.47TTTTTATAATTTTGYTCTTTTTGACTCCA . . Other Intron . PTGER3EX2 557 G 0.99 T0.01 0.03 TATAAATGATCTTGKTCTATTGGGGAGCG . . Other Intron . PTGER3EX2 628T 0.83 C 0.17 0.28 AACCACATACATCAYTGAAGACAAGGGAT . . Other Intron .PTGER3EX2 769 T 0.91 A 0.09 0.17 GTATAATGTATTTAWAATATTCATCGATA . . OtherIntron . PTGER3EX2 787 T 0.94 G 0.06 0.12 ATTCATCGATACCAKTATTCAAATATTGC. . Other Intron . PTGER3EX2 805 A 0.91 C 0.09 0.16TCAAATATTGCTCAMTACAGCAAATTAGC . . Other Intron . PTGER3EX2 850 G 0.98 A0.02 0.04 TTTAAGTTTACTTGRATTGATAATTAGGT . . Other Intron . PTGER3EX2 852T 0.62 A 0.38 0.47 TAAGTTTACTTGGAWTGATAATTAGGTTT . . Other Intron .PTGER3EX2 855 A 0.98 T 0.02 0.04 GTTTACTTGGATTGWTAATTAGGTTTACT . . OtherIntron . PTGER3EX3 76 C 0.94 T 0.06 0.12 CTCCACCTCCTTACYCTGCCAGT0TTCCTCCC CTC Nonsynonymous Pro Leu PTGER3EX3 80 C 0.93 T 0.07 0.13ACCTCCTTACCCTGYCAGTGTTCCTCAAC TGC TGT Synonymous Cys Cys PTGER3EX4 719 G0.84 T 0.16 0.27 TCTAAGCYTTTGATKACAAAGGAGTGATG . . Other 3′UTR .PTGER3EX4 94 C 0.98 T 0.03 0.05 TTTGCATATTTCTTYCCACCTGAGAAGGA . . Other3′UTR . PTGER3EX6 197 A 0.98 G 0.03 0.05 GAGTGCTGTGTTTTRAAAAAGCAAGCTCC .. Other 3′UTR . PTGER3EX6 300 G 0.91 A 0.09 0.16GAGATTACCAGCAARCCAGGTCATTTCCG . . Other 3′UTR . PTGER3EX6 387 T 0.98 A0.03 0.05 CCAATTTAGACTTAWAGTAAGAATAGCAC . . Other 3′UTR . PIGER3EX7 85 A0.98 G 0.02 0.04 TTGGTGCAGTTCTCRTGATAGTGAGTGAG CAT CGT Nonsynonymous HisArg PTGER3EX8 116 C 0.83 T 0.17 0.28 GATTTGTCCTTTCCYGCCATGTCTTCATC CCCCCT Synonymous Pro Pro PTGER3EX9 16 T 0.94 C 0.06 0.12TGCCTATCACATAAYAGGAGAACCCTGCA . . Other Intron . RENEX1 80 A TGGAAGCATGGATGGWTGGAGAAGGATGCC GGA GGT Synonymous Gly Gly RENEX2 135 A0.76 C 0.24 0.37 ATGAAGAGGCTGACMCTTGGCAACACCAC ACA ACC Synonymous ThrThr RENEX4 151 A 0.97 G 0.03 0.05 GACATCATCACCGTRAGTTGGGCCGCCCT . .Other Intron . RENEX4 165 T 0.66 G 0.34 0.45AAGTTGGGCCGCCCKAGGTCATCTGCCCC . . Other Intron . RENEX9 138 G 0.99 A0.01 0.03 TTCAGGTGAGGTTCRAGTCGGCCCCCTCG . . Other Intron . SAEX1 167 T0.91 C 0.09 0.17 GTTTTGGGCCAGTCYTGCTCCTCCGGATT Other Promoter . SAEX1 76G 0.98 T 0.03 0.05 ATTACCTGTAAGAGKAACCGCTGGGAGTC . . Synonymous OtherPromoter SAEX11 143 C 0.99 T 0.01 0.02 AGAGCAGATGATGTYATATTATCCTCTGG GTCGTT Synonymous Val Val SAEX2 54 T 0.94 C 0.06 0.12CTCTGTGCAAATCCYGAGTGCTAAAGCTT . . Other 5′UTR . SAEX3 109 T 0.99 C 0.010.03 GAGTTTTGAGGAACYGGGATCTCTGTCCA CTG CCG Nonsynonymous Leu Pro SAEX4187 T 0.82 C 0.18 0.30 CACTCCAAGCTGATYGTATCAGAGAACTC ATT ATC SynonymousVal Val SAEX5 182 T 0.14 C 0.86 0.24 TGGAAGGTATACTTYCACAAAAGTGCAGC . .Other Intron . SAEX8 111 G 0.97 C 0.03 0.06AAATGGAGAAACAASACGGGCCTGGATAT AAG AAC Nonsynonymous Lys Asn SAEX9 101 C0.98 T 0.03 0.05 CCTTCTCCTGCTTTYGATGTTAAGGTTTG TTC TTT Synonymous PhePhe SCNN1GEX1 167 G 0.48 A 0.52 0.50 GGTGGCCCAGGAAGRCGCAGCGCGGCCGG . .Other Promoter . SCNN1GEX1 236 G 0.81 T 0.19 0.30TGAAGTCGTGGCCCKCTCCGGGCGGTCTC . . Other Promoter . . SCNN1GEX1 498 G0.99 A 0.01 0.02 TGGAGCGGATGCCGRGCGCCAGGGCGTCG . . Other Intron . .SCNN1GEX1 552 C 0.70 G 0.30 0.42 GAGCCAGCATCAGCSGGTGGCGGCTTCCC . . OtherIntron . SCNN1GEX1 553 G 0.99 A 0.01 0.02 AGCCAGCATCAGCCRGTGGCGGCTTCCCG. . Other Intron . SCNN1GEX12 1016 T 0.80 A 0.20 0.32AGATCAGAGTGCCGWGGTGGAGGTCTGGG . . Other 3′UTR . SCNN1GEX12 1085 A 0.75 G0.25 0.38 CAGGAGATGGATTTRGTTATTCAATTTTG . . Other 3′UTR . SCNN1GEX12 407C 0.78 G 0.22 0.34 ATGCTGGATGAGCTSTGAGGCAGGGTTGA CTC CTG Synonymous LeuLeu SCNN1GEX12 454 G 0.99 T 0.01 0.02 GACCACCAGCCATGKTCTAAGGACATGGA . .Other 3′UTR . SCNN1GEX12 485 G 0.99 A 0.01 0.02GGGTGCCCCCAGACRTGTGCACAGGGGAC . . Other 3′UTR . SCNN10EX12 569 T 0.86 G0.14 0.24 CGCAAGATGGGGCCKGGGCATGCGCAGGA . . Other 3′UTR . SCNNIGEX12 646C 0.80 T 0.20 0.32 ATAAATCCCGGGACYTGAACTATTAGCAC . . Other 3′UTR .SCNN1GEX12 678 G 0.80 A 0.20 0.32 ACTAGAGACTGGGARCCGAGGCAGTGGTG . .Other 3′UTR . SCNN1GEX12 982 A 0.76 G 0.24 0.37GAGAACTGGCCCAGRGCCCTTGGAGTGTT . . Other 3′UTR . SCNN1GEX2 219 G 0.92 T0.08 0.14 TCGTGGTGTCCCGCKGCCGTCTGCGCCGC GGC TGC Nonsynonymous Gly CysSCNN1GEX2 26 G 0.16 C 0.84 0.27 TCTTCTTTGCCCCTSCAGCACGCCCGTCC . . OtherIntron . SCNN1GEX2 43 G 0.36 A 0.64 0.46 GCACGCCCGTCCTCRGAGTCCCGTCCTCA .. Other 5′UTR SCNN1GEX3 186 T 0.79 C 0.21 0.34TTCTCCCACCGGATYCCGCTGCTGATCTT ATT ATC Synonymous Ile Ile SCNN1GEX3 259 G0.94 A 0.06 0.12 GGAAGCGGAAAGTCRGCGGTAGCATCATT GGC AGC Nonsynonymous GlySer SCNN1GEX3 261 C 0.91 T 0.09 0.16 AAGCGGAAAGTCGGYGGTAGCATCATTCA GGCGGT Synonymous Gly Gly SCNN1GEX3 301 G 0.97 A 0.03 0.06ATGTCATGCACATCRAGTCCAAGCAAGTG GAG AAG Nonsynonymous Glu Lys SCNN1GEX3 99T 0.73 C 0.27 0.40 CTGAAGTCCCTGTAYGGCTTTCCAGAGTC TAT TAC Synonymous TyrTyr SCNN1GEX4 47 C 0.96 T 0.04 0.07 TCAAATGACACCTCYGACTGTGCCACCTA TCCTCT Synonymous Ser Ser SCNN1GEX7 142 G 0.70 A 0.30 0.42GGTAACAGATTGGCRGGGGCACCCAGCCC . . Other Intron . TBXA2REX1 518 T 0.89 A0.11 0.20 GCTGGGCCCGCCCCWGGTCACAGCCAGAC . . Other 5′UTR . TBXA2REX1B 130T 0.80 C 0.20 0.32 CTCAGCCTCCCGAGYAGCTGGGATTACAG . . Other 5′UTR .TBXA2REX2 292 T 0.98 A 0.02 0.04 TCCTCACCTTCCTCWGCGGCCTCGTCCTC TGC AGCNonsynonymous Cys Ser TBXA2REX2 329 T 0.98 A 0.03 0.05CCTGGGGCTGCTGGWGACCGGTACCATCG GTG GAG Nonsynonymous Val Glu TBXA2REX2333 C 0.96 T 0.04 0.08 GGGCTGCTGGTGACYGGTACCATCGTGGT ACC ACT SynonymousThr Thr TBXA2REX2 371 A 0.99 T 0.01 0.03 CGCCGCGCTCITCGWGTGGCACGCCGTGGGAG GTG Nonsynonymous Glu Val TBXA2REX2 390 T 0.94 A 0.06 0 12CACGCCGTGGACCCWGGCTGCCGTCTCTG CCT CCA Synonymous Pro Pro TBXA2REX2 525 G0.95 A 0.05 0.10 CCGGCGGTCGCCTCRCAGCGCCGCGCCTG TCG TCA Synonymous SerSer TBXA2REX2 568 G 0.99 A 0.01 0.02 TGGTGTGGGCGGCCRCGCTGGCGCTGGGC GCGACG Nonsynonymous Ala Thr TBXA2REX2 617 T 0.98 A 0.03 0.05GGGTCGCTACACCGWGCAATACCCGGGGT GTG GAG Nonsynonymous Val Glu TBXA2REX2739 G 0.96 A 0.04 0.07 TCCTGCTGAACACGRTCAGCGTGGCCACC GTC ATCNonsynonymous Val Ile TBXA2REX2 852 C 0.98 A 0.02 0.04ATCATGGTGGTGGCMAGCGTGTGTTGGCT GCC GCA Synonymous Ala Ala TBXA2REX3 145 T0.36 C 0.64 0.46 GACCCCTGGGTGTAYATCCTGTTCCGCCG TAT TAC Synonymous TyrTyr TBXA2REX3 358 A 0.93 G 0.07 0.13 GGGGTGCTGGATGGRCAGTGGGCATCAGC . .Other 3′UTR . TBXA2REX3 528 A 0.89 G 0.11 0.19AAGGGCATGCAGACRTTGGAAGAGGGTCT . . Other 3′UTR . TBXA2REX3 599 C 0.89 T0.11 0.20 CCCAGGCTGGAGTGYAGTGGCGCAATCTC . . Other 3′UTR . TBXA2REX3 701C 0.86 T 0.14 0.24 GGCGCGCGCCACCAYGCCCGGCTAATTTT . . Other 3′UTR .TBXA2REX3 904 A 0.70 G 0.30 0.42 TGGAGTACAGTGGCRCGATCTCGGCTCAC . . Other3′UTR . TBXA2REX3 906 G 0.53 A 0.47 0.50 GAGTACAGTGGCACRATCTCGGCTCACTG .. Other 3′UTR . TBXA2REX3 953 G 0.39 C 0.61 0.47TTCAAGCGATTCTCSTGCCTCAGCCTCCC . . Other 3′UTR . TBXASEX10 61 G 0.97 T0.03 0.06 CAGCCTCGAGGAAGKCCTGCCCTATCTGG GGC GTC Nonsynonymous Gly ValTBXASEX10 98 G 0.93 A 0.07 0.14 ATTGCAGAGACGCTRAGGATGTACCCGCC CTG CTASynonymous Leu Leu TBXASEX11 105 C 0.91 T 0.09 0.16GTGCTAGAGATGGCYGTGGGTGCCCTGCA GCC GCT Synonymous Ala Ala TBXASEX11 152 C0.99 A 0.01 0.03 GCCAAGCCCGGAGAMCTTCAACCCTGAAA ACC AAC Nonsynonymous ThrAsn TBXASEX11 49 C 0.98 G 0.02 0.05 CACGGGAGGCAGCTSAGGACTGCGAGGTG CAGGAG Synonymous Gln Glu TBXASEX11 73 C 0.99 T 0.01 0.02AGGTGCTGGGGCAGYGCATCCCCGCAGGC CGC TGC Nonsynonymous Arg Cys TBXASEX11 88G 0.90 A 0.10 0.18 GCATCCCCGCAGGCRCTGTGCTAGAGATG GCT ACT NonsynonymousAla Thr TBXASEX12 46 C 0.98 A 0.02 0.04 TCACGGCTGAGGCCMGGCAGCAGCACCGGCGG AGG Synonymous Arg Arg TBXASEX13 226 A 0.99 G 0.01 0.02CCTGGCATGCAAGGRTAAGAGGTTCTTTT . . Other 3′UTR . TBXASEX4 130 C 0.99 T0.01 0.03 CCAACAGAATGGTAYGTAGTTTTCTTTCC . . Other Intron . TBXASEX5 15 G0.99 A 0.01 0.02 CTGACCCTCTGCTTRTTACTTCCCAACAG . . Other Intron .TBXASEX6 59 C 0.98 A 0.02 0.04 AGCCAAGCCTGCGAMCTTCTCCTGGCTCA GAC GAASynonymous Asp Asp TBXASEX8 110 A 0.89 G 0.11 0.20ATGGCTTTTTTAACRAACTCATTAGGAAT AAA GAA Nonsynonymous Lys Asp TBXASEX8 119A 0.99 G 0.01 0.03 TTAACAAACTCATTRGGAATGTGATTGCC AGG GGG NonsynonymousArg Gly TBXASEX9 156 C 0.96 A 0.04 0.07 CGAACCCTTCCCGGMAACACCAGCCCAGCCAA AAA Nonsynonymous Gln Lys TBXASEX9 276 C 0.88 G 0.12 0.21CTTTTGCCACCTACSTACTGGCCACCAAC CTA GTA Nonsynonymous Leu Val TRHREX1 56 G0.44 C 0.56 0.49 TTCTGCAGAACTTASATGATAAGCAACGA . . Other Promoter .TRHREX1 84 T 0.98 C 0.02 0.04 ACAAAGCCAGCTGCYTCTAGACCCCTGGC . . OtherPromoter . TRHREX2 147 C 0.99 A 0.01 0.03 GTCAGTGAACTGAAMCAAACACAGCTTCAAAC AAA Nonsynonymous Asn. Lys TRHREX2 240 A 0.99 G 0.01 0.03GGCCTGGGCATTGTRGGCAACATCATGGT GTA GTG Synonymous Val Val TRHREX3 1161 T0.58 C 0.42 0.49 TCCCACATGATGGGYGGAAAAAGGCAAAA . . Other 3′UTR . TRHREX31231 T 0.98 C 0.03 0.05 TTAAATTTGAAAAGYATAGTCAAGACAAA . . Other 3′UTR .TRHREX3 1540 T 0.97 A 0.03 0.06 TTCTTTTTTTGTTTWTCTCAAATGCTAGT . . Other3′UTR . TRHREX3 1786 A 0.99 T 0.01 0.03 GAATCTCCGAGGGCWAAAATTGCCCTTGG .. Other 3′UTR . TRHREX3 1846 T 0.94 C 0.06 0.12GTAGATCAAAAAAGYACCCATACCTTTAC . . Other 3′UTR . TRHREX3 2046 G 0.98 A0.02 0.04 CCTCATTCTAGAGTRCGCTTTTTTTTTTT . . Other 3′UTR . TRHREX3 2175 A0.97 G 0.03 0.06 ACCTGCATGACAGTRAGCAATCTATGTTA . . Other 3′GlR TRHREX32283 G 0.95 A 0.05 0.10 ACAAGCACATGTGTRTTTATAAACACATA . . Other 3′UTR .TRHREX3 377 T 0.95 C 0.05 0.10 GCCACAAAAGTGTCYTTTGATGACACCTG TCT TCCSynonymous Ser Ser TRHREX3 960 T 0.96 C 0.04 0.07TAAGATTTTAGACAYACATGTTAACTGTA . . Other 3′UTR .

[0116] TABLE 2 Base Ref Alt Heterozygosity Ref Alt Type of amino Refamino Alt amino Gene/ExOn Position Allele Freq (P) Allele Freq (Q) (H)Sequence Tag Codon Codon acid change acid acid ACEEX13 138 C 0.81 T 0.190.30 CCTCTGCTGGTCCCYAGCCAGGAGGCATC CCC CCT Synonymous Pro Pro ACEEX17 52A 0.20 G 0.80 0.32 AATGTGATGGCCACRTCCCGGAAATATGA ACA ACG Synonymous ThrThr ADRB3EX1 416 T 0.90 C 0.10 0.18 TCGTGGCCATCGCCYGGACTCCGAGACTC TGGCGC Nonsynonymous Trp Arg AGTEX2 644 C 0.86 T 0.14 0.24GCTGCTGCTGTCCAYGGTGGTGGGCGTGT ACG ATG Nonsynonymous Thr Met AGTEX2 827 T0.10 C 0.90 0.18 TGGCTGCTCCCTGAYGGGAGCCAGTGTGG ATG ACT Nonsynonymous MerThr AGTEXP1 173 C 0.71 T 0.29 0.41 TGCTTGTGTGTTTTYCCCAGTGTCTATTA . .Other Promoter . AGTEXP2 203 G 0.86 A 0.14 0.24CTCGACCCTGCACCRGCTCACTCTGTTCA . . Other Promoter . AGTEXP3 144 C 0.24 A0.76 0.37 GCTATAAATAGGGCMTCGTGACCCGGCCA . . Other Promoter . ANPEX3 120T 0.91 C 0.09 0.16 GTCTCTGCTGCATTYGTGTCATCTTGTTG . . Other 3′UTR .ANPEX3 33 T 0.80 C 0.20 0.32 TCTCTTTGCAGTACYGAAGATAACAGCCA TGA AGANonsynonymous Stop Arg ATIEX5 1138 A 0.93 G 0.07 0.13AAGAAGCCTGCACCRTGTTTTGAGGTTGA CCA CCG Synonymous Pro Pro ATIEX5 1593 G0.88 T 0.12 0.21 AAAGTTTTCGTGCCKGTTTTCAGCTATTA . . Other 3′UTR . ATIEX5649 T 0.61 C 0.39 0.47 CAAAATTCAACCCTYCCGATAGGGCTGGG CTT CTC SynonymousLeu Leu MRLEX2 1504 C 0.89 T 0.11 0.20 CAAGAACCAGATGAYGGGAGCTATTACCC GACGAT Synonymous Asp Asp MRLEX2 545 A 0.81 G 0.19 0.30GCGTCATGCGCGCCRTTGTTAAAAGCCCT ATT GTT Nonsynonymous Ile Val NCXIEX123101 A 0.16 T 0.84 0.26 ACTCATTTTTTAGCWGTATTAGGAATGTC . . Other 3′UTR .

[0117] TABLE 3 Gene/Exon Gene Name Table 1 AADD Alpha-Adducin ACEAngiotensin Converting Enzyme ADDB Beta Adducin ADDG Gamma AdducinADORA2A A2a Adenosine Receptor ADRB3 Beta-3-Adrenergic Receptor ADROM(prepro)Adrenomedullin AEI Anion Exchanger AGT Angiotensinogen ALDREDAldose Reductase ANPEX1 Atrial Natriuretic Factor APOA1 ApolipoproteinA-I APOA2 Apolipoprotein A-II APOA4 Apolipoprotein A-IV APOC1EX1Apolipoprotein C-I APOC2 Apolipoprotein C-II APOC3 Apolipoprotein C-IIIAPOC4 Apolipoprotein C-IV APOER2 Apolipoprotein E Receptor 2 AT1Angiotensin II Receptor Type-1 AT2 Angiotensin II Receptor Type 2 AVPArginine Vasopressin AVPR2 Arginine Vasopressin Receptor Type II BIRBeta Inward Rectifier Subunit (Pancreatic K Channel) BKRB2 B2-BradykininReceptor BNP Brain Natriuretic Protein BRS3 Bombesin Receptor Subtype-3CAL/CGRP Calcitonin/Calcitonin Gene Related Peptide CHY Chymase CLCNKBChloride Channel (Human Kidney - B) CNP C-Type Natriuretic Peptide COX1Cyclooxygenase-1 COX2 Cyclooxygenase-2 CYP11B1 Cytochrome P-450 11 Beta1 CYP11B2 Cytochrome P-450 11 Beta 2 DBH Dopamine Beta-Hydroxylase DD1RDopamine D1 Receptor EDNRA Endothelin Receptor Subtype A EDNRBEndothelin Receptor Subtype B ELAM1 Endothelial Leukocyte AdhesionMolecule 1 ENDOTHEL Endothelin-2 ET1 Endothelin-1 GALNR Galanin ReceptorGGR Glucagon Receptor GH1 Growth Hormone 1 GH2 Growth Hormone 2 GIPRGlucose Insulinotropic Peptide Receptor or Gastric InhibitoryPolypeptide Receptor GLUT2 Glucose Transporter 2 GLUT4 GlucoseTransporter 4 GLUT5 Glucose Transport-Like 5 GNB3 G-Protein Beta-3 ChainGSY1 Glycogen Synthetase HAPT Haptoglobin HSD11K HydroxysteroidDehydrogenase 11 Beta Kidney Isozyme HSTSCGENE Homo sapiensThiazide-Sensitive Cotransporter HUMAPNH1A Human Na/H Antiporter HUMGFATHuman Glutamine:Fructose-6-Phosphate Amidotransferase HUMGLTRN HumanGlucose Transporter HUMGUANCYC Human Guanylate Cyclase IAPP IsletAmyloid Polypepode ICAM1 Intercellular Adhesion Molecule 1 ICAM2Intercellular Adhesion Molecule 2 INS Insulin KALST Kallistatin KLKKallilrein MRL Mineralocorticoid Receptor NCX1 Sodium-Calcium ExchangerNET Norepinephrine Transporter NPY Neuropeptide Y NPYR1 Neuropeptide YY1 Receptor PGIS Prostacyclin Synthase PLA2A Pancreatic PhospholipaseA-2 PNMT Phenylethanolamine N-Methyltransferase PPGLUC PreproglucagonPPTHR Preprothyrotropin-Releasing Hormone PTGER3 Prostaglandin EReceptor EP3 Subtype REN Renin SA SA Gene Acetyl-CoA SynthetaseHomologue ?? (a candidate gene for genetic hypertension SCNNIGAmiloride-Sensitive Epithelial Sodium Channel Gamma Subunit TBXA2RThromboxane A2 Receptor TBXASO Thromboxane Synthase TRHRThyrotropin-Releasing Hormone Receptor Table 2 ACE AngiotensinConverting Enzyme ADRB3 Beta-3-Adrenergic Receptor AGT AngiotensinogenANP Atrial Natriuretic Factor AT1 Angiotensin II Receptor Type-1 MRLMineralocorticoid Receptor NCX1 Sodium-Calcium Exchanger

What is claimed is:
 1. A nucleic acid of between 10 and 100 basescomprising at least 10 contiguous nucleotides including a polymorphicsite from a sequence shown in Table 1, column 8 or the complementthereof.
 2. The nucleic acid of claim 1 that is DNA.
 3. The nucleic acidof claim 1 that is RNA.
 4. The nucleic acid of claim 1 that is less than50 bases.
 5. The nucleic acid of claim 1 that is less than 20 bases. 6.The nucleic acid of claim 1, wherein the polymorphic form occupying thepolymorphic site is a reference base shown in Table 1, column
 3. 7. Thenucleic acid of claim 1, wherein the polymorphic form occupying thepolymorphic site is an alternative base shown in Table 1, column
 5. 8.The nucleic acid of claim 7, wherein the alternative base correlateswith hypertension or susceptibility thereto.
 9. The nucleic acid ofclaim 1, wherein the polymorphic site is one for which reference andalternative bases shown in columns 3 and 5 of Table 1 are respectivelycomponents of different codons encoding different amino acids.
 10. Thenucleic acid of claim 1, which is from a gene encoding a humanangiotensin I receptor.
 11. The nucleic acid of claim 1, which is from agene encoding an angiotensin II receptor.
 12. The nucleic acid of claim1, which is from a gene encoding an atrial natriuretic peptide.
 13. Thenucleic acid of claim 1, which is from a gene encoding a β-3-adrenergicreceptor.
 14. The nucleic acid of claim 1, which is from a gene encodinga bradykinin receptor B2.
 15. The nucleic acid of claim 1, which is froma gene encoding a mineralocorticoid receptor
 16. The nucleic acid ofclaim 1, which is from a gene encoding a renin protein.
 17. The nucleicacid of claim 1, which from a gene encoding an angiotensinogen protein.18. The nucleic acid of claim 1, which from a gene encoding a sodiumcalcium ion channel.
 19. The nucleic acid of claim 1, which is from agene encoding an angiotensin converting protein.
 20. The nucleic acid ofclaim 1, which is from a gene encoding an angiotensin convertingprotein.
 21. Allele-specific oligonucleotide that hybridizes to asequence including a polymorphic site shown in Table 1 or the complementthereof.
 22. The allele-specific oligonucleotide of claim 21 that is aprobe.
 23. An isolated nucleic acid comprising a sequence of Table 1,column 8 or the complement thereof, wherein the polymorphic site withinthe sequence or its complement is occupied by a base other than thereference base show in Table 1, column
 3. 24. A method of analyzing anucleic acid, comprising: obtaining the nucleic acid from an individual;and determining a base occupying any one of the polymorphic sites shownin Table 1 or other polymorphic sites in equilibrium dislinkagetherewith.
 25. The method of claim 24, wherein the determining comprisesdetermining a set of bases occupying a set of the polymorphic sitesshown in Table
 1. 26. The method of claim 25, wherein the nucleic acidis obtained from a plurality of individuals, and a base occupying one ofthe polymorphic positions is determined in each of the individuals, andthe method further comprising testing each individual for the presenceof a disease phenotype, and correlating the presence of the diseasephenotype with the base.
 27. The method of claim 24, wherein thedetermined base is correlated with susceptibility to hypertension.
 28. Amethod of diagnosing a phenotype comprising: determining whichpolymorphic form(s) are present in a sample from a subject at one ormore polymorphic sites shown in Table 1; diagnosing the presence of aphenotype correlated with the form(s) in the subject.
 29. The method ofclaim 28, wherein the phenotype is hypertension.
 30. A method ofscreening for a polymorphic site suitable for diagnosing a phenotype,comprising: identifying a polymorphic site linked to a polymorphic siteshown in Table 1, wherein a polymorphic form of the polymorphic siteshown in Table 1 has been correlated with a phenotype; and determininghaplotypes in a population of individuals to indicate whether the linkedpolymorphic site has a polymorphic form in equlibrium dislinkage withthe polymorphic form correlated with the phenotype.
 31. The method ofclaim 30, wherein the polymorphic form of the polymorphic site shown inTable I has been correlated with hypertension.
 32. The method of claim30, wherein the linked polymorphic site and the polymorphic site shownin Table 1 are from the same gene.
 33. A computer-readable storagemedium for storing data for access by an application program beingexecuted on a data processing system, comprising: a data structurestored in the computer-readable storage medium, the data structureincluding information resident in a database used by the applicationprogram and including: a plurality of records, each record of theplurality comprising information identifying a polymorphisms shown inTable
 1. 34. The computer-readable storage medium of claim 33, whereineach record has a field identifying a base occupying a polymorphic siteand a location of the polymorphic site.
 35. The computer-readablestorage medium of claim 33, wherein each record identifies a nucleicacid segment of between 10 and 100 bases from a fragment shown in Table1 including a polymorphic site, or the complement of the segment. 36.The computer-readable storage medium of claim 33, comprising at least 10records, each record comprising information identifying a differentpolymorphism shown in Table
 1. 37. The computer-readable storage mediumof claim 33, comprising at least 10 records, each record comprisinginformation identifying a different polymorphism shown in Table
 1. 38. Asignal carrying data for access by an application program being executedon a data processing system, comprising: a data structure encoded in thesignal, said data structure including information resident in a databaseused by the application program and including: a plurality of records,each record of the plurality comprising information identifying apolymorphism shown in Table 1